A few (more) diabetes papers of interest

Earlier this week I covered a couple of papers, but the second paper turned out to include a lot of interesting stuff so I decided to cut the post short and postpone my coverage of the other papers I’d intended to cover in that post until a later point in time; this post includes some of those other papers I’d intended to cover in that post.

i. TCF7L2 Genetic Variants Contribute to Phenotypic Heterogeneity of Type 1 Diabetes.

“Although the autoimmune destruction of β-cells has a major role in the development of type 1 diabetes, there is growing evidence that the differences in clinical, metabolic, immunologic, and genetic characteristics among patients (1) likely reflect diverse etiology and pathogenesis (2). Factors that govern this heterogeneity are poorly understood, yet these may have important implications for prognosis, therapy, and prevention.

The transcription factor 7 like 2 (TCF7L2) locus contains the single nucleotide polymorphism (SNP) most strongly associated with type 2 diabetes risk, with an ∼30% increase per risk allele (3). In a U.S. cohort, heterozygous and homozygous carriers of the at-risk alleles comprised 40.6% and 7.9%, respectively, of the control subjects and 44.3% and 18.3%, respectively, of the individuals with type 2 diabetes (3). The locus has no known association with type 1 diabetes overall (48), with conflicting reports in latent autoimmune diabetes in adults (816). […] Our studies in two separate cohorts have shown that the type 2 diabetes–associated TCF7L2 genetic variant is more frequent among specific subsets of individuals with autoimmune type 1 diabetes, specifically those with fewer markers of islet autoimmunity (22,23). These observations support a role of this genetic variant in the pathogenesis of diabetes at least in a subset of individuals with autoimmune diabetes. However, whether individuals with type 1 diabetes and this genetic variant have distinct metabolic abnormalities has not been investigated. We aimed to study the immunologic and metabolic characteristics of individuals with type 1 diabetes who carry a type 2 diabetes–associated allele of the TCF7L2 locus.”

“We studied 810 TrialNet participants with newly diagnosed type 1 diabetes and found that among individuals 12 years and older, the type 2 diabetes–associated TCF7L2 genetic variant is more frequent in those presenting with a single autoantibody than in participants who had multiple autoantibodies. These TCF7L2 variants were also associated with higher mean C-peptide AUC and lower mean glucose AUC levels at the onset of type 1 diabetes. […] These findings suggest that, besides the well-known link with type 2 diabetes, the TCF7L2 locus may play a role in the development of type 1 diabetes. The type 2 diabetes–associated TCF7L2 genetic variant identifies a subset of individuals with autoimmune type 1 diabetes and fewer markers of islet autoimmunity, lower glucose, and higher C-peptide at diagnosis. […] A possible interpretation of these data is that TCF7L2-encoded diabetogenic mechanisms may contribute to diabetes development in individuals with limited autoimmunity […]. Because the risk of progression to type 1 diabetes is lower in individuals with single compared with multiple autoantibodies, it is possible that in the absence of this type 2 diabetes–associated TCF7L2 variant, these individuals may have not manifested diabetes. If that is the case, we would postulate that disease development in these patients may have a type 2 diabetes–like pathogenesis in which islet autoimmunity is a significant component but not necessarily the primary driver.”

“The association between this genetic variant and single autoantibody positivity was present in individuals 12 years or older but not in children younger than 12 years. […] The results in the current study suggest that the type 2 diabetes–associated TCF7L2 genetic variant plays a larger role in older individuals. There is mounting evidence that the pathogenesis of type 1 diabetes varies by age (31). Younger individuals appear to have a more aggressive form of disease, with faster decline of β-cell function before and after onset of disease, higher frequency and severity of diabetic ketoacidosis, which is a clinical correlate of severe insulin deficiency, and lower C-peptide at presentation (3135). Furthermore, older patients are less likely to have type 1 diabetes–associated HLA alleles and islet autoantibodies (28). […] Taken together, we have demonstrated that individuals with autoimmune type 1 diabetes who carry the type 2 diabetes–associated TCF7L2 genetic variant have a distinct phenotype characterized by milder immunologic and metabolic characteristics than noncarriers, closer to those of type 2 diabetes, with an important effect of age.”

ii. Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes.

“Concerns about cardiovascular disease in type 2 diabetes have traditionally focused on atherosclerotic vasculo-occlusive events, such as myocardial infarction, stroke, and limb ischemia. However, one of the earliest, most common, and most serious cardiovascular disorders in patients with diabetes is heart failure (1). Following its onset, patients experience a striking deterioration in their clinical course, which is marked by frequent hospitalizations and eventually death. Many sudden deaths in diabetes are related to underlying ventricular dysfunction rather than a new ischemic event. […] Heart failure and diabetes are linked pathophysiologically. Type 2 diabetes and heart failure are each characterized by insulin resistance and are accompanied by the activation of neurohormonal systems (norepinephrine, angiotensin II, aldosterone, and neprilysin) (3). The two disorders overlap; diabetes is present in 35–45% of patients with chronic heart failure, whether they have a reduced or preserved ejection fraction.”

“Treatments that lower blood glucose do not exert any consistently favorable effect on the risk of heart failure in patients with diabetes (6). In contrast, treatments that increase insulin signaling are accompanied by an increased risk of heart failure. Insulin use is independently associated with an enhanced likelihood of heart failure (7). Thiazolidinediones promote insulin signaling and have increased the risk of heart failure in controlled clinical trials (6). With respect to incretin-based secretagogues, liraglutide increases the clinical instability of patients with existing heart failure (8,9), and the dipeptidyl peptidase 4 inhibitors saxagliptin and alogliptin are associated with an increased risk of heart failure in diabetes (10). The likelihood of heart failure with the use of sulfonylureas may be comparable to that with thiazolidinediones (11). Interestingly, the only two classes of drugs that ameliorate hyperinsulinemia (metformin and sodium–glucose cotransporter 2 inhibitors) are also the only two classes of antidiabetes drugs that appear to reduce the risk of heart failure and its adverse consequences (12,13). These findings are consistent with experimental evidence that insulin exerts adverse effects on the heart and kidneys that can contribute to heart failure (14). Therefore, physicians can prevent many cases of heart failure in type 2 diabetes by careful consideration of the choice of agents used to achieve glycemic control. Importantly, these decisions have an immediate effect; changes in risk are seen within the first few months of changes in treatment. This immediacy stands in contrast to the years of therapy required to see a benefit of antidiabetes drugs on microvascular risk.”

“As reported by van den Berge et al. (4), the prognosis of patients with heart failure has improved over the past two decades; heart failure with a reduced ejection fraction is a treatable disease. Inhibitors of the renin-angiotensin system are a cornerstone of the management of both disorders; they prevent the onset of heart failure and the progression of nephropathy in patients with diabetes, and they reduce the risk of cardiovascular death and hospitalization in those with established heart failure (3,15). Diabetes does not influence the magnitude of the relative benefit of ACE inhibitors in patients with heart failure, but patients with diabetes experience a greater absolute benefit from treatment (16).”

“The totality of evidence from randomized trials […] demonstrates that in patients with diabetes, heart failure is not only common and clinically important, but it can also be prevented and treated. This conclusion is particularly significant because physicians have long ignored heart failure in their focus on glycemic control and their concerns about the ischemic macrovascular complications of diabetes (1).”

iii. Closely related to the above study: Mortality Reduction Associated With β-Adrenoceptor Inhibition in Chronic Heart Failure Is Greater in Patients With Diabetes.

“Diabetes increases mortality in patients with chronic heart failure (CHF) and reduced left ventricular ejection fraction. Studies have questioned the safety of β-adrenoceptor blockers (β-blockers) in some patients with diabetes and reduced left ventricular ejection fraction. We examined whether β-blockers and ACE inhibitors (ACEIs) are associated with differential effects on mortality in CHF patients with and without diabetes. […] We conducted a prospective cohort study of 1,797 patients with CHF recruited between 2006 and 2014, with mean follow-up of 4 years.”

RESULTS Patients with diabetes were prescribed larger doses of β-blockers and ACEIs than were patients without diabetes. Increasing β-blocker dose was associated with lower mortality in patients with diabetes (8.9% per mg/day; 95% CI 5–12.6) and without diabetes (3.5% per mg/day; 95% CI 0.7–6.3), although the effect was larger in people with diabetes (interaction P = 0.027). Increasing ACEI dose was associated with lower mortality in patients with diabetes (5.9% per mg/day; 95% CI 2.5–9.2) and without diabetes (5.1% per mg/day; 95% CI 2.6–7.6), with similar effect size in these groups (interaction P = 0.76).”

“Our most important findings are:

  • Higher-dose β-blockers are associated with lower mortality in patients with CHF and LVSD, but patients with diabetes may derive more benefit from higher-dose β-blockers.

  • Higher-dose ACEIs were associated with comparable mortality reduction in people with and without diabetes.

  • The association between higher β-blocker dose and reduced mortality is most pronounced in patients with diabetes who have more severely impaired left ventricular function.

  • Among patients with diabetes, the relationship between β-blocker dose and mortality was not associated with glycemic control or insulin therapy.”

“We make the important observation that patients with diabetes may derive more prognostic benefit from higher β-blocker doses than patients without diabetes. These data should provide reassurance to patients and health care providers and encourage careful but determined uptitration of β-blockers in this high-risk group of patients.”

iv. Diabetes, Prediabetes, and Brain Volumes and Subclinical Cerebrovascular Disease on MRI: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

“Diabetes and prediabetes are associated with accelerated cognitive decline (1), and diabetes is associated with an approximately twofold increased risk of dementia (2). Subclinical brain pathology, as defined by small vessel disease (lacunar infarcts, white matter hyperintensities [WMH], and microhemorrhages), large vessel disease (cortical infarcts), and smaller brain volumes also are associated with an increased risk of cognitive decline and dementia (37). The mechanisms by which diabetes contributes to accelerated cognitive decline and dementia are not fully understood, but contributions of hyperglycemia to both cerebrovascular disease and primary neurodegenerative disease have been suggested in the literature, although results are inconsistent (2,8). Given that diabetes is a vascular risk factor, brain atrophy among individuals with diabetes may be driven by increased cerebrovascular disease. Brain magnetic resonance imaging (MRI) provides a noninvasive opportunity to study associations of hyperglycemia with small vessel disease (lacunar infarcts, WMH, microhemorrhages), large vessel disease (cortical infarcts), and brain volumes (9).”

“Overall, the mean age of participants [(n = 1,713)] was 75 years, 60% were women, 27% were black, 30% had prediabetes (HbA1c 5.7 to <6.5%), and 35% had diabetes. Compared with participants without diabetes and HbA1c <5.7%, those with prediabetes (HbA1c 5.7 to <6.5%) were of similar age (75.2 vs. 75.0 years; P = 0.551), were more likely to be black (24% vs. 11%; P < 0.001), have less than a high school education (11% vs. 7%; P = 0.017), and have hypertension (71% vs. 63%; P = 0.012) (Table 1). Among participants with diabetes, those with HbA1c <7.0% versus ≥7.0% were of similar age (75.4 vs. 75.1 years; P = 0.481), but those with diabetes and HbA1c ≥7.0% were more likely to be black (39% vs. 28%; P = 0.020) and to have less than a high school education (23% vs. 16%; P = 0.031) and were more likely to have a longer duration of diabetes (12 vs. 8 years; P < 0.001).”

“Compared with participants without diabetes and HbA1c <5.7%, those with diabetes and HbA1c ≥7.0% had smaller total brain volume (β −0.20 SDs; 95% CI −0.31, −0.09) and smaller regional brain volumes, including frontal, temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus (all P < 0.05) […]. Compared with participants with diabetes and HbA1c <7.0%, those with diabetes and HbA1c ≥7.0% had smaller total brain volume (P < 0.001), frontal lobe volume (P = 0.012), temporal lobe volume (P = 0.012), occipital lobe volume (P = 0.008), parietal lobe volume (P = 0.015), deep gray matter volume (P < 0.001), Alzheimer disease signature region volume (0.031), and hippocampal volume (P = 0.016). Both participants with diabetes and HbA1c <7.0% and those with prediabetes (HbA1c 5.7 to <6.5%) had similar total and regional brain volumes compared with participants without diabetes and HbA1c <5.7% (all P > 0.05). […] No differences in the presence of lobar microhemorrhages, subcortical microhemorrhages, cortical infarcts, and lacunar infarcts were observed among the diabetes-HbA1c categories (all P > 0.05) […]. Compared with participants without diabetes and HbA1c <5.7%, those with diabetes and HbA1c ≥7.0% had increased WMH volume (P = 0.016). The WMH volume among participants with diabetes and HbA1c ≥7.0% was also significantly greater than among those with diabetes and HbA1c <7.0% (P = 0.017).”

“Those with diabetes duration ≥10 years were older than those with diabetes duration <10 years (75.9 vs. 75.0 years; P = 0.041) but were similar in terms of race and sex […]. Compared with participants with diabetes duration <10 years, those with diabetes duration ≥10 years has smaller adjusted total brain volume (β −0.13 SDs; 95% CI −0.20, −0.05) and smaller temporal lobe (β −0.14 SDs; 95% CI −0.24, −0.03), parietal lobe (β − 0.11 SDs; 95% CI −0.21, −0.01), and hippocampal (β −0.16 SDs; 95% CI −0.30, −0.02) volumes […]. Participants with diabetes duration ≥10 years also had a 2.44 times increased odds (95% CI 1.46, 4.05) of lacunar infarcts compared with those with diabetes duration <10 years”.

In this community-based population, we found that ARIC-NCS participants with diabetes with HbA1c ≥7.0% have smaller total and regional brain volumes and an increased burden of WMH, but those with prediabetes (HbA1c 5.7 to <6.5%) and diabetes with HbA1c <7.0% have brain volumes and markers of subclinical cerebrovascular disease similar to those without diabetes. Furthermore, among participants with diabetes, those with more-severe disease (as measured by higher HbA1c and longer disease duration) had smaller total and regional brain volumes and an increased burden of cerebrovascular disease compared with those with lower HbA1c and shorter disease duration. However, we found no evidence that associations of diabetes with smaller brain volumes are mediated by cerebrovascular disease.

The findings of this study extend the current literature that suggests that diabetes is strongly associated with brain volume loss (11,2527). Global brain volume loss (11,2527) has been consistently reported, but associations of diabetes with smaller specific brain regions have been less robust (27,28). Similar to prior studies, the current results show that compared with individuals without diabetes, those with diabetes have smaller total brain volume (11,2527) and regional brain volumes, including frontal and occipital lobes, deep gray matter, and the hippocampus (25,27). Furthermore, the current study suggests that greater severity of disease (as measured by HbA1c and diabetes duration) is associated with smaller total and regional brain volumes. […] Mechanisms whereby diabetes may contribute to brain volume loss include accelerated amyloid-β and hyperphosphorylated tau deposition as a result of hyperglycemia (29). Another possible mechanism involves pancreatic amyloid (amylin) infiltration of the brain, which then promotes amyloid-β deposition (29). […] Taken together, […] the current results suggest that diabetes is associated with both lower brain volumes and increased cerebrovascular pathology (WMH and lacunes).”

v. Interventions to increase attendance for diabetic retinopathy screening (Cochrane review).

“The primary objective of the review was to assess the effectiveness of quality improvement (QI) interventions that seek to increase attendance for DRS in people with type 1 and type 2 diabetes.

Secondary objectives were:
To use validated taxonomies of QI intervention strategies and behaviour change techniques (BCTs) to code the description of interventions in the included studies and determine whether interventions that include particular QI strategies or component BCTs are more effective in increasing screening attendance;
To explore heterogeneity in effect size within and between studies to identify potential explanatory factors for variability in effect size;
To explore differential effects in subgroups to provide information on how equity of screening attendance could be improved;
To critically appraise and summarise current evidence on the resource use, costs and cost effectiveness.”

“We included 66 RCTs conducted predominantly (62%) in the USA. Overall we judged the trials to be at low or unclear risk of bias. QI strategies were multifaceted and targeted patients, healthcare professionals or healthcare systems. Fifty-six studies (329,164 participants) compared intervention versus usual care (median duration of follow-up 12 months). Overall, DRS [diabetic retinopathy screening] attendance increased by 12% (risk difference (RD) 0.12, 95% confidence interval (CI) 0.10 to 0.14; low-certainty evidence) compared with usual care, with substantial heterogeneity in effect size. Both DRS-targeted (RD 0.17, 95% CI 0.11 to 0.22) and general QI interventions (RD 0.12, 95% CI 0.09 to 0.15) were effective, particularly where baseline DRS attendance was low. All BCT combinations were associated with significant improvements, particularly in those with poor attendance. We found higher effect estimates in subgroup analyses for the BCTs ‘goal setting (outcome)’ (RD 0.26, 95% CI 0.16 to 0.36) and ‘feedback on outcomes of behaviour’ (RD 0.22, 95% CI 0.15 to 0.29) in interventions targeting patients, and ‘restructuring the social environment’ (RD 0.19, 95% CI 0.12 to 0.26) and ‘credible source’ (RD 0.16, 95% CI 0.08 to 0.24) in interventions targeting healthcare professionals.”

“Ten studies (23,715 participants) compared a more intensive (stepped) intervention versus a less intensive intervention. In these studies DRS attendance increased by 5% (RD 0.05, 95% CI 0.02 to 0.09; moderate-certainty evidence).”

“Overall, we found that there is insufficient evidence to draw robust conclusions about the relative cost effectiveness of the interventions compared to each other or against usual care.”

“The results of this review provide evidence that QI interventions targeting patients, healthcare professionals or the healthcare system are associated with meaningful improvements in DRS attendance compared to usual care. There was no statistically significant difference between interventions specifically aimed at DRS and those which were part of a general QI strategy for improving diabetes care.”

vi. Diabetes in China: Epidemiology and Genetic Risk Factors and Their Clinical Utility in Personalized Medication.

“The incidence of type 2 diabetes (T2D) has rapidly increased over recent decades, and T2D has become a leading public health challenge in China. Compared with European descents, Chinese patients with T2D are diagnosed at a relatively young age and low BMI. A better understanding of the factors contributing to the diabetes epidemic is crucial for determining future prevention and intervention programs. In addition to environmental factors, genetic factors contribute substantially to the development of T2D. To date, more than 100 susceptibility loci for T2D have been identified. Individually, most T2D genetic variants have a small effect size (10–20% increased risk for T2D per risk allele); however, a genetic risk score that combines multiple T2D loci could be used to predict the risk of T2D and to identify individuals who are at a high risk. […] In this article, we review the epidemiological trends and recent progress in the understanding of T2D genetic etiology and further discuss personalized medicine involved in the treatment of T2D.”

“Over the past three decades, the prevalence of diabetes in China has sharply increased. The prevalence of diabetes was reported to be less than 1% in 1980 (2), 5.5% in 2001 (3), 9.7% in 2008 (4), and 10.9% in 2013, according to the latest published nationwide survey (5) […]. The prevalence of diabetes was higher in the senior population, men, urban residents, individuals living in economically developed areas, and overweight and obese individuals. The estimated prevalence of prediabetes in 2013 was 35.7%, which was much higher than the estimate of 15.5% in the 2008 survey. Similarly, the prevalence of prediabetes was higher in the senior population, men, and overweight and obese individuals. However, prediabetes was more prevalent in rural residents than in urban residents. […] the 2013 survey also compared the prevalence of diabetes among different races. The crude prevalence of diabetes was 14.7% in the majority group, i.e., Chinese Han, which was higher than that in most minority ethnic groups, including Tibetan, Zhuang, Uyghur, and Muslim. The crude prevalence of prediabetes was also higher in the Chinese Han ethnic group. The Tibetan participants had the lowest prevalence of diabetes and prediabetes (4.3% and 31.3%).”

“[T]he prevalence of diabetes in young people is relatively high and increasing. The prevalence of diabetes in the 20- to 39-year age-group was 3.2%, according to the 2008 national survey (4), and was 5.9%, according to the 2013 national survey (5). The prevalence of prediabetes also increased from 9.0% in 2008 to 28.8% in 2013 […]. Young people suffering from diabetes have a higher risk of chronic complications, which are the major cause of mortality and morbidity in diabetes. According to a study conducted in Asia (6), patients with young-onset diabetes had higher mean concentrations of HbA1c and LDL cholesterol and a higher prevalence of retinopathy (20% vs. 18%, P = 0.011) than those with late-onset diabetes. In the Chinese, patients with early-onset diabetes had a higher risk of nonfatal cardiovascular disease (7) than did patients with late-onset diabetes (odds ratio [OR] 1.91, 95% CI 1.81–2.02).”

“As approximately 95% of patients with diabetes in China have T2D, the rapid increase in the prevalence of diabetes in China may be attributed to the increasing rates of overweight and obesity and the reduction in physical activity, which is driven by economic development, lifestyle changes, and diet (3,11). According to a series of nationwide surveys conducted by the China Physical Fitness Surveillance Center (12), the prevalence of overweight (BMI ≥23.0 to <27.5 kg/m2) in Chinese adults aged 20–59 years increased from 37.4% in 2000 to 39.2% in 2005, 40.7% in 2010, and 41.2% in 2014, with an estimated increase of 0.27% per year. The prevalence of obesity (BMI ≥27.5 kg/m2) increased from 8.6% in 2000 to 10.3% in 2005, 12.2% in 2010, and 12.9% in 2014, with an estimated increase of 0.32% per year […]. The prevalence of central obesity increased from 13.9% in 2000 to 18.3% in 2005, 22.1% in 2010, and 24.9% in 2014, with an estimated increase of 0.78% per year. Notably, T2D develops at a considerably lower BMI in the Chinese population than that in European populations. […] The relatively high risk of diabetes at a lower BMI could be partially attributed to the tendency toward visceral adiposity in East Asian populations, including the Chinese population (13). Moreover, East Asian populations have been found to have a higher insulin sensitivity with a much lower insulin response than European descent and African populations, implying a lower compensatory β-cell function, which increases the risk of progressing to overt diabetes (14).”

“Over the past two decades, linkage analyses, candidate gene approaches, and large-scale GWAS have successfully identified more than 100 genes that confer susceptibility to T2D among the world’s major ethnic populations […], most of which were discovered in European populations. However, less than 50% of these European-derived loci have been successfully confirmed in East Asian populations. […] there is a need to identify specific genes that are associated with T2D in other ethnic populations. […] Although many genetic loci have been shown to confer susceptibility to T2D, the mechanism by which these loci participate in the pathogenesis of T2D remains unknown. Most T2D loci are located near genes that are related to β-cell function […] most single nucleotide polymorphisms (SNPs) contributing to the T2D risk are located in introns, but whether these SNPs directly modify gene expression or are involved in linkage disequilibrium with unknown causal variants remains to be investigated. Furthermore, the loci discovered thus far collectively account for less than 15% of the overall estimated genetic heritability.”

“The areas under the receiver operating characteristic curves (AUCs) are usually used to assess the discriminative accuracy of an approach. The AUC values range from 0.5 to 1.0, where an AUC of 0.5 represents a lack of discrimination and an AUC of 1 represents perfect discrimination. An AUC ≥0.75 is considered clinically useful. The dominant conventional risk factors, including age, sex, BMI, waist circumference, blood pressure, family history of diabetes, physical activity level, smoking status, and alcohol consumption, can be combined to construct conventional risk factor–based models (CRM). Several studies have compared the predictive capacities of models with and without genetic information. The addition of genetic markers to a CRM could slightly improve the predictive performance. For example, one European study showed that the addition of an 11-SNP GRS to a CRM marginally improved the risk prediction (AUC was 0.74 without and 0.75 with the genetic markers, P < 0.001) in a prospective cohort of 16,000 individuals (37). A meta-analysis (38) consisting of 23 studies investigating the predictive performance of T2D risk models also reported that the AUCs only slightly increased with the addition of genetic information to the CRM (median AUC was increased from 0.78 to 0.79). […] Despite great advances in genetic studies, the clinical utility of genetic information in the prediction, early identification, and prevention of T2D remains in its preliminary stage.”

“An increasing number of studies have highlighted that early nutrition has a persistent effect on the risk of diabetes in later life (40,41). China’s Great Famine of 1959–1962 is considered to be the largest and most severe famine of the 20th century […] Li et al. (43) found that offspring of mothers exposed to the Chinese famine have a 3.9-fold increased risk of diabetes or hyperglycemia as adults. A more recent study (the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors [SPECT-China]) conducted in 2014, among 6,897 adults from Shanghai, Jiangxi, and Zhejiang provinces, had the same conclusion that famine exposure during the fetal period (OR 1.53, 95% CI 1.09–2.14) and childhood (OR 1.82, 95% CI 1.21–2.73) was associated with diabetes (44). These findings indicate that undernutrition during early life increases the risk of hyperglycemia in adulthood and this association is markedly exaggerated when facing overnutrition in later life.”


February 23, 2018 Posted by | Cardiology, Diabetes, Epidemiology, Genetics, Health Economics, Immunology, Medicine, Neurology, Ophthalmology, Pharmacology, Studies | Leave a comment

Endocrinology (part 5 – calcium and bone metabolism)

Some observations from chapter 6:

“*Osteoclasts – derived from the monocytic cells; resorb bone. *Osteoblasts – derived from the fibroblast-like cells; make bone. *Osteocytes – buried osteoblasts; sense mechanical strain in bone. […] In order to ensure that bone can undertake its mechanical and metabolic functions, it is in a constant state of turnover […] Bone is laid down rapidly during skeletal growth at puberty. Following this, there is a period of stabilization of bone mass in early adult life. After the age of ~40, there is a gradual loss of bone in both sexes. This occurs at the rate of approximately 0.5% annually. However, in ♀ after the menopause, there is a period of rapid bone loss. The accelerated loss is maximal in the first 2-5 years after the cessation of ovarian function and then gradually declines until the previous gradual rate of loss is once again established. The excess bone loss associated with the menopause is of the order of 10% of skeletal mass. This menopause-associated loss, coupled with higher peak bone mass acquisition in ♂, largely explains why osteoporosis and its associated fractures are more common in ♀.”

“The clinical utility of routine measurements of bone turnover markers is not yet established. […] Skeletal radiology[:] *Useful for: *Diagnosis of fracture. *Diagnosis of specific diseases (e.g. Paget’s disease and osteomalacia). *Identification of bone dysplasia. *Not useful for assessing bone density. […] Isotope bone scans are useful for identifying localized areas of bone disease, such as fracture, metastases, or Paget’s disease. […] Isotope bone scans are particularly useful in Paget’s disease to establish the extent and sites of skeletal involvement and the underlying disease activity. […] Bone biopsy is occasionally necessary for the diagnosis of patients with complex metabolic bone diseases. […] Bone biopsy is not indicated for the routine diagnosis of osteoporosis. It should only be undertaken in highly specialist centres with appropriate expertise. […] Measurement of 24h urinary excretion of calcium provides a measure of risk of renal stone formation or nephrocalcinosis in states of chronic hypercalcaemia. […] 250H vitamin D […] is the main storage form of vitamin D, and the measurement of ‘total vitamin D’ is the most clinically useful measure of vitamin D status. Internationally, there remains controversy around a ‘normal’ or ‘optimal’ concentration of vitamin D. Levels over 50nmol/L are generally accepted as satisfactory and values <25nmol/L representing deficiency. True osteomalacia occurs with vitamin D values <15 nmol/L. Low levels of 250HD can result from a variety of causes […] Bone mass is quoted in terms of the number of standard deviations from an expected mean. […] A reduction of one SD in bone density will approximately double the risk of fracture.”

[I should perhaps add a cautionary note here that while this variable is very useful in general, it is more useful in some contexts than in others; and in some specific disease process contexts it is quite clear that it will tend to underestimate the fracture risk. Type 1 diabetes is a clear example. For more details, see this post.]

“Hypercalcaemia is found in 5% of hospital patients and in 0.5% of the general population. […] Many different disease states can lead to hypercalcaemia. […] In asymptomatic community-dwelling subjects, the vast majority of hypercalcaemia is the result of hyperparathyroidism. […] The clinical features of hypercalcaemia are well recognized […]; unfortunately, they are non-specific […] [They include:] *Polyuria. *Polydipsia. […] *Anorexia. *Vomiting. *Constipation. *Abdominal pain. […] *Confusion. *Lethargy. *Depression. […] Clinical signs of hypercalcaemia are rare. […] the presence of bone pain or fracture and renal stones […] indicate the presence of chronic hypercalcaemia. […] Hypercalcaemia is usually a late manifestation of malignant disease, and the primary lesion is usually evident by the time hypercalcaemia is expressed (50% of patients die within 30 days).”

“Primary hyperparathyroidism [is] [p]resent in up to 1 in 500 of the general population where it is predominantly a disease of post-menopausal ♀ […] The normal physiological response to hypocalcaemia is an increase in PTH secretion. This is termed 2° hyperparathyroidism and is not pathological in as much as the PTH secretion remains under feedback control. Continued stimulation of the parathyroid glands can lead to autonomous production of PTH. This, in turn, causes hypercalcaemia which is termed tertiary hyperparathyroidism. This is usually seen in the context of renal disease […] In majority of patients [with hyperparathyroidism] without end-organ damage, disease is benign and stable. […] Investigation is, therefore, primarily aimed at determining the presence of end-organ damage from hypercalcaemia in order to determine whether operative intervention is indicated. […] It is generally accepted that all patients with symptomatic hyperparathyroidism or evidence of end-organ damage should be considered for parathyroidectomy. This would include: *Definite symptoms of hypercalcaemia. […] *Impaired renal function. *Renal stones […] *Parathyroid bone disease, especially osteitis fibrosis cystica. *Pancreatitis. […] Patients not managed with surgery require regular follow-up. […] <5% fail to become normocalcaemic [after surgery], and these should be considered for a second operation. […] Patients rendered permanently hypoparathyroid by surgery require lifelong supplements of active metabolites of vitamin D with calcium. This can lead to hypercalciuria, and the risk of stone formation may still be present in these patients. […] In hypoparathyroidism, the target serum calcium should be at the low end of the reference range. […] any attempt to raise the plasma calcium well into the normal range is likely to result in unacceptable hypercalciuria”.

“Although hypocalcaemia can result from failure of any of the mechanisms by which serum calcium concentration is maintained, it is usually the result of either failure of PTH secretion or because of the inability to release calcium from bone. […] The clinical features of hypocalcaemia are largely as a result of neuromuscular excitability. In order of  severity, these include: *Tingling – especially of fingers, toes, or lips. *Numbness – especially of fingers, toes, or lips. *Cramps. *Carpopedal spasm. *Stridor due to laryngospasm. *Seizures. […] symptoms of hypocalcaemia tend to reflect the severity and rapidity of onset of the metabolic abnormality. […] there may be clinical signs and symptoms associated with the underlying condition: *Vitamin D deficiency may be associated with generalized bone pain, fractures, or proximal myopathy […] *Hypoparathyroidism can be accompanied by mental slowing and personality disturbances […] *If hypocalcaemia is present during the development of permanent teeth, these may show areas of enamel hypoplasia. This can be a useful physical sign, indicating that the hypocalcaemia is long-standing. […] Acute symptomatic hypocalcaemia is a medical emergency and demands urgent treatment whatever the cause […] *Patients with tetany or seizures require urgent IV treatment with calcium gluconate […] Care must be taken […] as too rapid elevation of the plasma calcium can cause arrhythmias. […] *Treatment of chronic hypocalcaemia is more dependent on the cause. […] In patients with mild parathyroid dysfunction, it may be possible to achieve acceptable calcium concentrations by using calcium supplements alone. […] The majority of patients will not achieve adequate control with such treatment. In those cases, it is necessary to use vitamin D or its metabolites in pharmacological doses to maintain plasma calcium.”

“Pseudohypoparathyroidism[:] *Resistance to parathyroid hormone action. *Due to defective signalling of PTH action via cell membrane receptor. *Also affects TSH, LH, FSH, and GH signalling. […] Patients with the most common type of pseudohypoparathyroidism (type 1a) have a characteristic set of skeletal abnormalities, known as Albright’s hereditary osteodystrophy. This comprises: *Short stature. *Obesity. *Round face. *Short metacarpals. […] The principles underlying the treatment of pseudohypoparathyroidism are the same as those underlying hypoparathyroidism. *Patients with the most common form of pseudohypoparathyroidism may have resistance to the action of other hormones which rely on G protein signalling. They, therefore, need to be assessed for thyroid and gonadal dysfunction (because of defective TSH and gonadotrophin action). If these deficiencies are present, they need to be treated in the conventional manner.”

“Osteomalacia occurs when there is inadequate mineralization of mature bone. Rickets is a disorder of the growing skeleton where there is inadequate mineralization of bone as it is laid down at the epiphysis. In most instances, osteomalacia leads to build-up of excessive unmineralized osteoid within the skeleton. In rickets, there is build-up of unmineralized osteoid in the growth plate. […] These two related conditions may coexist. […] Clinical features [of osteomalacia:] *Bone pain. *Deformity. *Fracture. *Proximal myopathy. *Hypocalcaemia (in vitamin D deficiency). […] The majority of patients with osteomalacia will show no specific radiological abnormalities. *The most characteristic abnormality is the Looser’s zone or pseudofracture. If these are present, they are virtually pathognomonic of osteomalacia. […] Oncogenic osteomalacia[:] Certain tumours appear to be able to produce FGF23 which is phosphaturic. This is rare […] Clinically, such patients usually present with profound myopathy as well as bone pain and fracture. […] Complete removal of the tumour results in resolution of the biochemical and skeletal abnormalities. If this is not possible […], treatment with vitamin D metabolites and phosphate supplements […] may help the skeletal symptoms.”

Hypophosphataemia[:] Phosphate is important for normal mineralization of bone. In the absence of sufficient phosphate, osteomalacia results. […] In addition, phosphate is important in its own right for neuromuscular function, and profound hypophosphataemia can be accompanied by encephalopathy, muscle weakness, and cardiomyopathy. It must be remembered that, as phosphate is primarily an intracellular anion, a low plasma phosphate does not necessarily represent actual phosphate depletion. […] Mainstay [of treatment] is phosphate replacement […] *Long-term administration of phosphate supplements stimulates parathyroid activity. This can lead to hypercalcaemia, a further fall in phosphate, with worsening of the bone disease […] To minimize parathyroid stimulation, it is usual to give one of the active metabolites of vitamin D in conjunction with phosphate.”

“Although the term osteoporosis refers to the reduction in the amount of bony tissue within the skeleton, this is generally associated with a loss of structural integrity of the internal architecture of the bone. The combination of both these changes means that osteoporotic bone is at high risk of fracture, even after trivial injury. […] Historically, there has been a primary reliance on bone mineral density as a threshold for treatment, whereas currently there is far greater emphasis on assessing individual patients’ risk of fracture that incorporates multiple clinical risk factors as well as bone mineral density. […] Osteoporosis may arise from a failure of the body to lay down sufficient bone during growth and maturation; an earlier than usual onset of bone loss following maturity; or an rate of that loss. […] Early menopause or late puberty (in ♂ or ♀) is associated with risk of osteoporosis. […] Lifestyle factors affecting bone mass [include:] *weight-bearing exercise [increase bone mass] […] *Smoking. *Excessive alcohol. *Nulliparity. *Poor calcium nutrition. [These all decrease bone mass] […] The risk of osteoporotic fracture increases with age. Fracture rates in ♂ are approximately half of those seen in ♀ of the same age. An ♀ aged 50 has approximately a 1:2 chance [risk, surely… – US] of sustaining an osteoporotic fracture in the rest of her life. The corresponding figure for a ♂ is 1:5. […] One-fifth of hip fracture victims will die within 6 months of the injury, and only 50% will return to their previous level of independence.”

“Any fracture, other than those affecting fingers, toes, or face, which is caused by a fall from standing height or less is called a fragility (low-trauma) fracture, and underlying osteoporosis should be considered. Patients suffering such a fracture should be considered for investigation and/or treatment for osteoporosis. […] [Osteoporosis is] [u]sually clinically silent until an acute fracture. *Two-thirds of vertebral fractures do not come to clinical attention. […] Osteoporotic vertebral fractures only rarely lead to neurological impairment. Any evidence of spinal cord compression should prompt a search for malignancy or other underlying cause. […] Osteoporosis does not cause generalized skeletal pain. […] Biochemical markers of bone turnover may be helpful in the calculation of fracture risk and in judging the response to drug therapies, but they have no role in the diagnosis of osteoporosis. […] An underlying cause for osteoporosis is present in approximately 10-30% of women and up to 50% of men with osteoporosis. […] 2° causes of osteoporosis are more common in ♂ and need to be excluded in all ♂ with osteoporotic fracture. […] Glucocorticoid treatment is one of the major 2° causes of osteoporosis.”

February 22, 2018 Posted by | Books, Cancer/oncology, Diabetes, Epidemiology, Medicine, Nephrology, Neurology, Pharmacology | Leave a comment

Prevention of Late-Life Depression (II)

Some more observations from the book:

In contrast to depression in childhood and youth when genetic and developmental vulnerabilities play a significant role in the development of depression, the development of late-life depression is largely attributed to its interactions with acquired factors, especially medical illness [17, 18]. An analysis of the WHO World Health Survey indicated that the prevalence of depression among medical patients ranged from 9.3 to 23.0 %, significantly higher than that in individuals without medical conditions [19]. Wells et al. [20] found in the Epidemiologic Catchment Area Study that the risk of developing lifetime psychiatric disorders among individuals with at least one medical condition was 27.9 % higher than among those without medical conditions. […] Depression and disability mutually reinforce the risk of each other, and adversely affect disease progression and prognosis [21, 25]. […] disability caused by medical conditions serves as a risk factor for depression [26]. When people lose their normal sensory, motor, cognitive, social, or executive functions, especially in a short period of time, they can become very frustrated or depressed. Inability to perform daily tasks as before decreases self-esteem, reduces independence, increases the level of psychological stress, and creates a sense of hopelessness. On the other hand, depression increases the risk for disability. Negative interpretation, attention bias, and learned hopelessness of depressed persons may increase risky health behaviors that exacerbate physical disorders or disability. Meanwhile, depression-related cognitive impairment also affects role performance and leads to functional disability [25]. For example, Egede [27] found in the 1999 National Health Interview Survey that the risk of having functional disability among patients with the comorbidity of diabetes and depression were approximately 2.5–5 times higher than those with either depression or diabetes alone. […]  A leading cause of disability among medical patients is pain and pain-related fears […] Although a large proportion of pain complaints can be attributed to physiological changes from physical disorders, psychological factors (e.g., attention, interpretation, and coping skills) play an important role in perception of pain […] Bair et al. [31] indicated in a literature review that the prevalence of pain was higher among depressed patients than non-depressed patients, and the prevalence of major depression was also higher among pain patients comparing to those without pain complaints.”

Alcohol use has more serious adverse health effects on older adults than other age groups, since aging-related physiological changes (e.g. reduced liver detoxification and renal clearance) affect alcohol metabolism, increase the blood concentration of alcohol, and magnify negative consequences. More importantly, alcohol interacts with a variety of frequently prescribed medications potentially influencing both treatment and adverse effects. […] Due to age-related changes in pharmacokinetics and pharmacodynamics, older adults are a vulnerable population to […] adverse drug effects. […] Adverse drug events are frequently due to failure to adjust dosage or to account for drug–drug interactions in older adults [64]. […] Loneliness […] is considered as an independent risk factor for depression [46, 47], and has been demonstrated to be associated with low physical activity, increased cardiovascular risks, hyperactivity of the hypothalamic-pituitary-adrenal axis, and activation of immune response [for details, see Cacioppo & Patrick’s book on these topics – US] […] Hopelessness is a key concept of major depression [54], and also an independent risk factor of suicidal ideation […] Hopelessness reduces expectations for the future, and negatively affects judgment for making medical and behavioral decisions, including non-adherence to medical regimens or engaging in unhealthy behaviors.”

Co-occurring depression and medical conditions are associated with more functional impairment and mortality than expected from the severity of the medical condition alone. For example, depression accompanying diabetes confers increased functional impairment [27], complications of diabetes [65, 66], and mortality [6771]. Frasure-Smith and colleagues highlighted the prognostic importance of depression among persons who had sustained a myocardial infarction (MI), finding that depression was a significant predictor of mortality at both 6 and 18 months post MI [72, 73]. Subsequent follow-up studies have borne out the increased risk conferred by depression on the mortality of patients with cardiovascular disease [10, 74, 75]. Over the course of a 2-year follow-up interval, depression contributed as much to mortality as did myocardial infarction or diabetes, with the population attributable fraction of mortality due to depression approximately 13 % (similar to the attributable risk associated with heart attack at 11 % and diabetes at 9 %) [76]. […] Although the bidirectional relationship between physical disorders and depression has been well known, there are still relatively few randomized controlled trials on preventing depression among medically ill patients. […] Rates of attrition [in post-stroke depression prevention trials has been observed to be] high […] Stroke, acute coronary syndrome, cancer, and other conditions impose a variety of treatment burdens on patients so that additional interventions without direct or immediate clinical effects may not be acceptable [95]. So even with good participation rates, lack of adherence to the intervention might limit effects.”

Late-life depression (LLD) is a heterogeneous disease, with multiple risk factors, etiologies, and clinical features. It has been recognized for many years that there is a significant relationship between the presence of depression and cerebrovascular disease in older adults [1, 2]. This subtype of LLD was eventually termed “vascular depression.” […] There have been a multitude of studies associating white matter abnormalities with depression in older adults using MRI technology to visualize lesions, or what appear as hyperintensities in the white matter on T2-weighted scans. A systematic review concluded that white matter hyperintensities (WMH) are more common and severe among older adults with depression compared to their non-depressed peers [9]. […] WMHs are associated with older age [13] and cerebrovascular risk factors, including diabetes, heart disease, and hypertension [14–17]. White matter severity and extent of WMH volume has been related to the severity of depression in late life [18, 19]. For example, among 639 older, community-dwelling adults, white matter lesion (WML) severity was found to predict depressive episodes and symptoms over a 3-year period [19]. […] Another way of investigating white matter integrity is with diffusion tensor imaging (DTI), which measures the diffusion of water in tissues and allows for indirect evidence of the microstructure of white matter, most commonly represented as fractional anisotropy (FA) and mean diffusivity (MD). DTI may be more sensitive to white matter pathology than is quantification of WMH […] A number of studies have found lower FA in widespread regions among individuals with LLD relative to controls [34, 36, 37]. […] lower FA has been associated with poorer performance on measures of cognitive functioning among patients with LLD [35, 38–40] and with measures of cerebrovascular risk severity. […] It is important to recognize that FA reflects the organization of fiber tracts, including fiber density, axonal diameter, or myelination in white matter. Thus, lower FA can result from multiple pathophysiological sources [42, 43]. […] Together, the aforementioned studies provide support for the vascular depression hypothesis. They demonstrate that white matter integrity is reduced in patients with LLD relative to controls, is somewhat specific to regions important for cognitive and emotional functioning, and is associated with cognitive functioning and depression severity. […] There is now a wealth of evidence to support the association between vascular pathology and depression in older age. While the etiology of depression in older age is multifactorial, from the epidemiological, neuroimaging, behavioral, and genetic evidence available, we can conclude that vascular depression represents one important subtype of LLD. The mechanisms underlying the relationship between vascular pathology and depression are likely multifactorial, and may include disrupted connections between key neural regions, reduced perfusion of blood to key brain regions integral to affective and cognitive processing, and inflammatory processes.”

Cognitive changes associated with depression have been the focus of research for decades. Results have been inconsistent, likely as a result of methodological differences in how depression is diagnosed and cognitive functioning measured, as well as the effects of potential subtypes and the severity of depression […], though deficits in executive functioning, learning and memory, and attention have been associated with depression in most studies [75]. In older adults, additional confounding factors include the potential presence of primary degenerative disorders, such as Alzheimer’s disease, which can pose a challenge to differential diagnosis in its early stages. […] LLD with cognitive dysfunction has been shown to result in greater disability than depressive symptoms alone [6], and MCI [mild cognitive impairment, US] with co-occurring LLD has been shown to double the risk of developing Alzheimer’s disease (AD) compared to MCI alone [86]. The conversion from MCI to AD also appears to occur earlier in patients with cooccurring depressive symptoms, as demonstrated by Modrego & Ferrandez [86] in their prospective cohort study of 114 outpatients diagnosed with amnestic MCI. […] Given accruing evidence for abnormal functioning of a number of cortical and subcortical networks in geriatric depression, of particular interest is whether these abnormalities are a reflection of the actively depressed state, or whether they may persist following successful resolution of symptoms. To date, studies have investigated this question through either longitudinal investigation of adults with geriatric depression, or comparison of depressed elders who are actively depressed versus those who have achieved symptom remission. Of encouragement, successful treatment has been reliably associated with normalization of some aspects of disrupted network functioning. For example, successful antidepressant treatment is associated with reduction of the elevated cerebral glucose metabolism observed during depressed states (e.g., [71–74]), with greater symptom reduction associated with greater metabolic change […] Taken together, these studies suggest that although a subset of the functional abnormalities observed during the LLD state may resolve with successful treatment, other abnormalities persist and may be tied to damage to the structural connectivity in important affective and cognitive networks. […] studies suggest a chronic decrement in cognitive functioning associated with LLD that is not adequately addressed through improvement of depressive symptoms alone.”

A review of the literature on evidence-based treatments for LLD found that about 50 % of patients improved on antidepressants, but that the number needed to treat (NNT) was quite high (NNT = 8, [139]) and placebo effects were significant [140]. Additionally, no difference was demonstrated in the effectiveness of one antidepressant drug class over another […], and in one-third of patients, depression was resistant to monotherapy [140]. The addition of medications or switching within or between drug classes appears to result in improved treatment response for these patients [140, 141]. A meta-analysis of patient-level variables demonstrated that duration of depressive symptoms and baseline depression severity significantly predicts response to antidepressant treatment in LLD, with chronically depressed older patients with moderate-to-severe symptoms at baseline experiencing more improvement in symptoms than mildly and acutely depressed patients [142]. Pharmacological treatment response appears to range from incomplete to poor in LLD with co-occurring cognitive impairment.”

“[C]ompared to other formulations of prevention, such as primary, secondary, or tertiary — in which interventions are targeted at the level of disease/stage of disease — the IOM conceptual framework involves interventions that are targeted at the level of risk in the population [2]. […] [S]elective prevention studies have an important “numbers” advantage — similar to that of indicated prevention trials: the relatively high incidence of depression among persons with key risk markers enables investigator to test interventions with strong statistical power, even with somewhat modest sample sizes. This fact was illustrated by Schoevers and colleagues [3], in which the authors were able to account for nearly 50 % of total risk of late-life depression with consideration of only a handful of factors. Indeed, research, largely generated by groups in the Netherlands and the USA, has identified that selective prevention may be one of the most efficient approaches to late-life depression prevention, as they have estimated that targeting persons at high risk for depression — based on risk markers such as medical comorbidity, low social support, or physical/functional disability — can yield theoretical numbers needed to treat (NNTs) of approximately 5–7 in primary care settings [4–7]. […] compared to the findings from selective prevention trials targeting older persons with general health/medical problems, […] trials targeting older persons based on sociodemographic risk factors have been more mixed and did not reveal as consistent a pattern of benefits for selective prevention of depression.”

Few of the studies in the existing literature that involve interventions to prevent depression and/or reduce depressive symptoms in older populations have included economic evaluations [13]. The identification of cost-effective interventions to provide to groups at high risk for depression is an important public health goal, as such treatments may avert or reduce a significant amount of the disease burden. […] A study by Katon and colleagues [8] showed that elderly patients with either subsyndromal or major depression had significantly higher medical costs during the previous 6 months than those without depression; total healthcare costs were $1,045 to $1,700 greater, and total outpatient/ambulatory costs ranged from being $763 to $979 more, on average. Depressed patients had greater usage of health resources in every category of care examined, including those that are not mental health-related, such as emergency department visits. No difference in excess costs was found between patients with a DSM-IV depressive disorder and those with depressive symptoms only, however, as mean total costs were 51 % higher in the subthreshold depression group (95 % CI = 1.39–1.66) and 49 % higher in the MDD/dysthymia group (95 % CI = 1.28–1.72) than in the nondepressed group [8]. In a similar study, the usage of various types of health services by primary care patients in the Netherlands was assessed, and average costs were determined to be 1,403 more in depressed individuals versus control patients [21]. Study investigators once again observed that patients with depression had greater utilization of both non-mental and mental healthcare services than controls.”

“In order for routine depression screening in the elderly to be cost-effective […] appropriate follow-up measures must be taken with those who screen positive, including a diagnostic interview and/or referral to a mental health professional [this – the necessity/requirement of proper follow-up following screens in order for screening to be cost-effective – is incidentally a standard result in screening contexts, see also Juth & Munthe’s book – US] [23, 25]. For example, subsequent steps may include initiation of psychotherapy or antidepressant treatment. Thus, one reason that the USPSTF does not recommend screening for depression in settings where proper mental health resources do not exist is that the evidence suggests that outcomes are unlikely to improve without effective follow-up care […]  as per the USPSTF suggestion, Medicare will only cover the screening when the appropriate supports for proper diagnosis and treatment are available […] In order to determine which interventions to prevent and treat depression should be provided to those who screen positive for depressive symptoms and to high-risk populations in general, cost-effectiveness analyses must be completed for a variety of different treatments and preventive measures. […] questions remain regarding whether annual versus other intervals of screening are most cost-effective. With respect to preventive interventions, the evidence to date suggests that these are cost-effective in settings where those at the highest risk are targeted.”

February 19, 2018 Posted by | Books, Cardiology, Diabetes, Health Economics, Neurology, Pharmacology, Psychiatry, Psychology | Leave a comment

Peripheral Neuropathy (I)

The objective of this book is to update health care professionals on recent advances in the pathogenesis, diagnosis and treatment of peripheral neuropathy. This work was written by a group of clinicians and scientists with large expertise in the field.

The book is not the first book about this topic I’ve read, so a lot of the stuff included was of course review – however it’s a quite decent text, and I decided to blog it in at least some detail anyway. It’s somewhat technical and it’s probably not a very good introduction to this topic if you know next to nothing about neurology – in that case I’m certain Said’s book (see the ‘not’-link above) is a better option.

I have added some observations from the first couple of chapters below. As InTech publications like these explicitly encourage people to share the ideas and observations included in these books, I shall probably cover the book in more detail than I otherwise would have.

“Within the developing world, infectious diseases [2-4] and trauma [5] are the most common sources of neuropathic pain syndromes. The developed world, in contrast, suffers more frequently from diabetic polyneuropathy (DPN) [6, 7], post herpetic neuralgia (PHN) from herpes zoster infections [8], and chemotherapy-induced peripheral neuropathy (CIPN) [9, 10]. There is relatively little epidemiological data regarding the prevalence of neuropathic pain within the general population, but a few estimates suggest it is around 7-8% [11, 12]. Despite the widespread occurrence of neuropathic pain, treatment options are limited and often ineffective […] Neuropathic pain can present as on-going or spontaneous discomfort that occurs in the absence of any observable stimulus or a painful hypersensitivity to temperature and touch. […] people with chronic pain have increased incidence of anxiety and depression and reduced scores in quantitative measures of health related quality of life [15]. Despite significant progress in chronic and neuropathic pain research, which has led to the discovery of several efficacious treatments in rodent models, pain management in humans remains ineffective and insufficient [16]. The lack of translational efficiency may be due to inadequate animal models that do not faithfully recapitulate human disease or from biological differences between rodents and humans […] In an attempt to increase the efficacy of medical treatment for neuropathic pain, clinicians and researchers have been moving away from an etiology based classification towards one that is mechanism based. It is current practice to diagnose a person who presents with neuropathic pain according to the underlying etiology and lesion topography [17]. However, this does not translate to effective patient care as these classification criteria do not suggest efficacious treatment. A more apt diagnosis might include a description of symptoms and the underlying pathophysiology associated with those symptoms.”

Neuropathic pain has been defined […] as “pain arising as the direct consequence of a lesion or disease affecting the somatosensory system” [18]. This is distinct from nociceptive pain – which signals tissue damage through an intact nervous system – in underlying pathophysiology, severity, and associated psychological comorbidities [13]. Individuals who suffer from neuropathic pain syndromes report pain of higher intensity and duration than individuals with non-neuropathic chronic pain and have significantly increased incidence of depression, anxiety, and sleep disorders [13, 19]. […] individuals with seemingly identical diseases who both develop neuropathic pain may experience distinct abnormal sensory phenotypes. This may include a loss of sensory perception in some modalities and increased activity in others. Often a reduction in the perception of vibration and light touch is coupled with positive sensory symptoms such as paresthesia, dysesthesia, and pain[20]. Pain may manifest as either spontaneous, with a burning or shock-like quality, or as a hypersensitivity to mechanical or thermal stimuli [21]. This hypersensitivity takes two forms: allodynia, pain that is evoked from a normally non-painful stimulus, and hyperalgesia, an exaggerated pain response from a moderately painful stimulus. […] Noxious stimuli are perceived by small diameter peripheral neurons whose free nerve endings are distributed throughout the body. These neurons are distinct from, although anatomically proximal to, the low threshold mechanoreceptors responsible for the perception of vibration and light touch.”

In addition to hypersensitivity, individuals with neuropathic pain frequently experience ongoing spontaneous pain as a major source of discomfort and distress. […] In healthy individuals, a quiescent neuron will only generate an action potential when presented with a stimulus of sufficient magnitude to cause membrane depolarization. Following nerve injury, however, significant changes in ion channel expression, distribution, and kinetics lead to disruption of the homeostatic electric potential of the membrane resulting in oscillations and burst firing. This manifests as spontaneous pain that has a shooting or burning quality […] There is reasonable evidence to suggest that individual ion channels contribute to specific neuropathic pain symptoms […] [this observation] provides an intriguing therapeutic possibility: unambiguous pharmacologic ion channel blockers to relieve individual sensory symptoms with minimal unintended effects allowing pain relief without global numbness. […] Central sensitization leads to painful hypersensitivity […] Functional and structural changes of dorsal horn circuitry lead to pain hypersensitivity that is maintained independent of peripheral sensitization [38]. This central sensitization provides a mechanistic explanation for the sensory abnormalities that occur in both acute and chronic pain states, such as the expansion of hypersensitivity beyond the innervation territory of a lesion site, repeated stimulation of a constant magnitude leading to an increasing pain response, and pain outlasting a peripheral stimulus [39-41]. In healthy individuals, acute pain triggers central sensitization, but homeostatic sensitivity returns following clearance of the initial insult. In some individuals who develop neuropathic pain, genotype and environmental factors contribute to maintenance of central sensitization leading to spontaneous pain, hyperalgesia, and allodynia. […] Similarly, facilitation also results in a lowered activation threshold in second order neurons”.

“Chronic pain conditions are associated with vast functional and structural changes of the brain, when compared to healthy controls, but it is currently unclear which comes first: does chronic pain cause distortions of brain circuitry and anatomy or do cerebral abnormalities trigger and/or maintain the perception of chronic pain? […] Brain abnormalities in chronic pain states include modification of brain activity patterns, localized decreases in gray matter volume, and circuitry rerouting [53]. […] Chronic pain conditions are associated with localized reduction in gray matter volume, and the topography of gray matter volume reduction is dictated, at least in part, by the particular pathology. […] These changes appear to represent a form of plasticity as they are reversible when pain is effectively managed [63, 67, 68].”

“By definition, neuropathic pain indicates direct pathology of the nervous system while nociceptive pain is an indication of real or potential tissue damage. Due to the distinction in pathophysiology, conventional treatments prescribed for nociceptive pain are not very effective in treating neuropathic pain and vice versa [78]. Therefore the first step towards meaningful pain relief is an accurate diagnosis. […] Treating neuropathic pain requires a multifaceted approach that aims to eliminate the underlying etiology, when possible, and manage the associated discomforts and emotional distress. Although in some cases it is possible to directly treat the cause of neuropathic pain, for example surgery to alleviate a constricted nerve, it is more likely that the primary cause is untreatable, as is the case with singular traumatic events such as stroke and spinal cord injury and diseases like diabetes. When this is the case, symptom management and pain reduction become the primary focus. Unfortunately, in most cases complete elimination of pain is not a feasible endpoint; a pain reduction of 30% is considered to be efficacious [21]. Additionally, many pharmacological treatments require careful titration and tapering to prevent adverse effects and toxicity. This process may take several weeks to months, and ultimately the drug may be ineffective, necessitating another trial with a different medication. It is therefore necessary that both doctor and patient begin treatment with realistic expectations and goals.”

First-line medications for the treatment of neuropathic pain are those that have proven efficacy in randomized clinical trials (RCTs) and are consistent with pooled clinical observations [81]. These include antidepressants, calcium channel ligands, and topical lidocaine [15]. Tricyclic antidepressants (TCAs) have demonstrated efficacy in treating neuropathic pain with positive results in RCTs for central post-stroke pain, PHN, painful diabetic and non-diabetic polyneuropathy, and post-mastectomy pain syndrome [82]. However they do not seem to be effective in treating painful HIV-neuropathy or CIPN [82]. Duloxetine and venlafaxine, two selective serotonin norepinephrine reuptake inhibitors (SSNRIs), have been found to be effective in DPN and both DPN and painful polyneuropathies, respectively [81]. […] Gabapentin and pregabalin have also demonstrated efficacy in several neuropathic pain conditions including DPN and PHN […] Topical lidocaine (5% patch or gel) has significantly reduced allodynia associated with PHN and other neuropathic pain syndromes in several RCTs [81, 82]. With no reported systemic adverse effects and mild skin irritation as the only concern, lidocaine is an appropriate choice for treating localized peripheral neuropathic pain. In the event that first line medications, alone or in combination, are not effective at achieving adequate pain relief, second line medications may be considered. These include opioid analgesics and tramadol, pharmaceuticals which have proven efficacy in RCTs but are associated with significant adverse effects that warrant cautious prescription [15]. Although opioid analgesics are effective pain relievers in several types of neuropathic pain [81, 82, 84], they are associated with misuse or abuse, hypogonadism, constipation, nausea, and immunological changes […] Careful consideration should be given when prescribing opiates to patients who have a personal or family history of drug or alcohol abuse […] Deep brain stimulation, a neurosurgical technique by which an implanted electrode delivers controlled electrical impulses to targeted brain regions, has demonstrated some efficacy in treating chronic pain but is not routinely employed due to a high risk-to-benefit ratio [91]. […] A major challenge in treating neuropathic pain is the heterogeneity of disease pathogenesis within an individual etiological classification. Patients with seemingly identical diseases may experience completely different neuropathic pain phenotypes […] One of the biggest barriers to successful management of neuropathic pain has been the lack of understanding in the underlying pathophysiology that produces a pain phenotype. To that end, significant progress has been made in basic science research.”

In diabetes mellitus, nerves and their supporting cells are subjected to prolonged hyperglycemia and metabolic disturbances and this culminates in reversible/irreversible nervous system dysfunction and damage, namely diabetic peripheral neuropathy (DPN). Due to the varying compositions and extents of neurological involvements, it is difficult to obtain accurate and thorough prevalence estimates of DPN, rendering this microvascular complication vastly underdiagnosed and undertreated [1-4]. According to American Diabetes Association, DPN occurs to 60-70% of diabetic individuals [5] and represents the leading cause of peripheral neuropathies among all cases [6, 7].”

A quick remark: This number seems really high to me. I won’t rule out that it’s accurate if you go with highly sensitive measures of neuropathy, but the number of patients who will experience significant clinical sequelae as a result of DPN is in my opinion likely to be significantly lower than that. On a peripherally related note, it should however on the other hand also be kept in mind that although diabetes-related neurological complications may display some clustering in patient groups – which will necessarily decrease the magnitude of the problem – no single test will ever completely rule out neurological complications in a diabetic; a patient with a negative Semmes-Weinstein monofilament test may still have autonomic neuropathy. So assessing the full disease burden in the context of diabetes-related neurological complications cannot be done using only a single instrument, and the full disease burden is likely to be higher than individual estimates encountered in the literature (unless a full neurological workup was done, which is unlikely to be the case). They do go into more detail about subgroups, clinical significance, etc. below, but I thought this observation was important to add early on in this part of the coverage.

Because diverse anatomic distributions and fiber types may be differentially affected in patients with diabetes, the disease manifestations, courses and pathologies of clinical and subclinical DPN are rather heterogeneous and encompass a broad spectrum […] Current consensus divides diabetes-associated somatic neuropathic syndromes into the focal/multifocal and diffuse/generalized neuropathies [6, 14]. The first category comprises a group of asymmetrical, acute-in-onset and self-limited single lesion(s) of nerve injury or impairment largely resulting from the increased vulnerability of diabetic nerves to mechanical insults (Carpal Tunnel Syndrome) […]. Such mononeuropathies occur idiopathically and only become a clinical problem in association with aging in 5-10% of those affected. Therefore, focal neuropathies are not extensively covered in this chapter [16]. The rest of the patients frequently develop diffuse neuropathies characterized by symmetrical distribution, insidious onset and chronic progression. In particular, a distal symmetrical sensorimotor polyneuropathy accounts for 90% of all DPN diagnoses in type 1 and type 2 diabetics and affects all types of peripheral sensory and motor fibers in a temporally non-uniform manner [6, 17].
Symptoms begin with prickling, tingling, numbness, paresthesia, dysesthesia and various qualities of pain associated with small sensory fibers at the very distal end (toes) of lower extremities [1, 18]. Presence of the above symptoms together with abnormal nociceptive response of epidermal C and A-δ fibers to pain/temperature (as revealed by clinical examination) constitute the diagnosis of small fiber sensory neuropathy, which produces both painful and insensate phenotypes [19]. Painful diabetic neuropathy is a prominent, distressing and chronic experience in at least 10-30% of DPN populations [20, 21]. Its occurrence does not necessarily correlate with impairment in electrophysiological or quantitative sensory testing (QST). […] Large myelinated sensory fibers that innervate the dermis, such as Aβ, also become involved later on, leading to impaired proprioception, vibration and tactile detection, and mechanical hypoalgesia [19]. Following this “stocking-glove”, length-dependent and dying-back evolvement, neurodegeneration gradually proceeds to proximal muscle sensory and motor nerves. Its presence manifests in neurological testings as reduced nerve impulse conductions, diminished ankle tendon reflex, unsteadiness and muscle weakness [1, 24].
Both the absence of protective sensory response and motor coordination predispose neuropathic foot to impaired wound healing and gangrenous ulceration — often ensued by limb amputation in severe and/or advanced cases […]. Although symptomatic motor deficits only appear in later stages of DPN [25], motor denervation and distal atrophy can increase the rate of fractures by causing repetitive minor trauma or falls [24, 28]. Other unusual but highly disabling late sequelae of DPN include limb ischemia and joint deformity [6]; the latter also being termed Charcot’s neuroarthropathy or Charcot’s joints [1]. In addition to significant morbidities, several separate cohort studies provided evidence that DPN [29], diabetic foot ulcers [30] and increased toe vibration perception threshold (VPT) [31] are all independent risk factors for mortality.”

Unfortunately, current therapy for DPN is far from effective and at best only delays the onset and/or progression of the disease via tight glucose control […] Even with near normoglycemic control, a substantial proportion of patients still suffer the debilitating neurotoxic consequences of diabetes [34]. On the other hand, some with poor glucose control are spared from clinically evident signs and symptoms of neuropathy for a long time after diagnosis [37-39]. Thus, other etiological factors independent of hyperglycemia are likely to be involved in the development of DPN. Data from a number of prospective, observational studies suggested that older age, longer diabetes duration, genetic polymorphism, presence of cardiovascular disease markers, malnutrition, presence of other microvascular complications, alcohol and tobacco consumption, and higher constitutional indexes (e.g. weight and height) interact with diabetes and make for strong predictors of neurological decline [13, 32, 40-42]. Targeting some of these modifiable risk factors in addition to glycemia may improve the management of DPN. […] enormous efforts have been devoted to understanding and intervening with the molecular and biochemical processes linking the metabolic disturbances to sensorimotor deficits by studying diabetic animal models. In return, nearly 2,200 articles were published in PubMed central and at least 100 clinical trials were reported evaluating the efficacy of a number of pharmacological agents; the majority of them are designed to inhibit specific pathogenic mechanisms identified by these experimental approaches. Candidate agents have included aldose reductase inhibitors, AGE inhibitors, γ-linolenic acid, α-lipoic acid, vasodilators, nerve growth factor, protein kinase Cβ inhibitors, and vascular endothelial growth factor. Notwithstanding a fruitful of knowledge and promising results in animals, none has translated into definitive clinical success […] Based on the records published by National Institute of Neurological Disorders and Stroke (NINDS), a main source of DPN research, about 16,488 projects were funded at the expense of over $8 billion for the fiscal years of 2008 through 2012. Of these projects, an estimated 72,200 animals were used annually to understand basic physiology and disease pathology as well as to evaluate potential drugs [255]. As discussed above, however, the usefulness of these pharmaceutical agents developed through such a pipeline in preventing or reducing neuronal damage has been equivocal and usually halted at human trials due to toxicity, lack of efficacy or both […]. Clearly, the pharmacological translation from our decades of experimental modeling to clinical practice with regard to DPN has thus far not even [been] close to satisfactory.”

Whereas a majority of the drugs investigated during preclinical testing executed experimentally desired endpoints without revealing significant toxicity, more than half that entered clinical evaluation for treating DPN were withdrawn as a consequence of moderate to severe adverse events even at a much lower dose. Generally, using other species as surrogates for human population inherently encumbers the accurate prediction of toxic reactions for several reasons […] First of all, it is easy to dismiss drug-induced non-specific effects in animals – especially for laboratory rodents who do not share the same size, anatomy and physical activity with humans. […]  Second, some physiological and behavioral phenotypes observable in humans are impossible for animals to express. In this aspect, photosensitive skin rash and pain serve as two good examples of non-translatable side effects. Rodent skin differs from that of humans in that it has a thinner and hairier epidermis and distinct DNA repair abilities [260]. Therefore, most rodent stains used in diabetes modeling provide poor estimates for the probability of cutaneous hypersensitivity reactions to pharmacological treatments […] Another predicament is to assess pain in rodents. The reason for this is simple: these animals cannot tell us when, where or even whether they are experiencing pain […]. Since there is not any specific type of behavior to which painful reaction can be unequivocally associated, this often leads to underestimation of painful side effects during preclinical drug screening […] The third problem is that animals and humans have different pharmacokinetic and toxicological responses.”

“Genetic or chemical-induced diabetic rats or mice have been a major tool for preclinical pharmacological evaluation of potential DPN treatments. Yet, they do not faithfully reproduce many neuropathological manifestations in human diabetics. The difficulty of such begins with the fact that it is not possible to obtain in rodents a qualitative and quantitative expression of the clinical symptoms that are frequently presented in neuropathic diabetic patients, including spontaneous pain of different characteristics (e.g. prickling, tingling, burning, squeezing), paresthesia and numbness. As symptomatic changes constitute an important parameter of therapeutic outcome, this may well underlie the failure of some aforementioned drugs in clinical trials despite their good performance in experimental tests […] Development of nerve dysfunction in diabetic rodents also does not follow the common natural history of human DPN. […] Besides the lack of anatomical resemblance, the changes in disease severity are often missing in these models. […] importantly, foot ulcers that occur as a late complication to 15% of all individuals with diabetes [14] do not spontaneously develop in hyperglycemic rodents. Superimposed injury by experimental procedure in the foot pads of diabetic rats or mice may lend certain insight in the impaired wound healing in diabetes [278] but is not reflective of the chronic, accumulating pathological changes in diabetic feet of human counterparts. Another salient feature of human DPN that has not been described in animals is the predominant sensory and autonomic nerve damage versus minimal involvement of motor fibers [279]. This should elicit particular caution as the selective susceptibility is critical to our true understanding of the etiopathogenesis underlying distal sensorimotor polyneuropathy in diabetes. In addition to the lack of specificity, most animal models studied only cover a narrow spectrum of clinical DPN and have not successfully duplicated syndromes including proximal motor neuropathy and focal lesions [279].
Morphologically, fiber atrophy and axonal loss exist in STZ-rats and other diabetic rodents but are much milder compared to the marked degeneration and loss of myelinated and unmyelinated nerves readily observed in human specimens [280]. Of significant note, rodents are notoriously resistant to developing some of the histological hallmarks seen in diabetic patients, such as segmental and paranodal demyelination […] the simultaneous presence of degenerating and regenerating fibers that is characteristic of early DPN has not been clearly demonstrated in these animals [44]. Since such dynamic nerve degeneration/regeneration signifies an active state of nerve repair and is most likely to be amenable to therapeutic intervention, absence of this property makes rodent models a poor tool in both deciphering disease pathogenesis and designing treatment approaches […] With particular respect to neuroanatomy, a peripheral axon in humans can reach as long as one meter [296] whereas the maximal length of the axons innervating the hind limb is five centimeters in mice and twelve centimeters in rats. This short length makes it impossible to study in rodents the prominent length dependency and dying-back feature of peripheral nerve dysfunction that characterizes human DPN. […] For decades the cytoarchitecture of human islets was assumed to be just like those in rodents with a clear anatomical subdivision of β-cells and other cell types. By using confocal microscopy and multi-fluorescent labeling, it was finally uncovered that human islets have not only a substantially lower percentage of β-cell population, but also a mixed — rather than compartmentalized — organization of the different cell types [297]. This cellular arrangement was demonstrated to directly alter the functional performance of human islets as opposed to rodent islets. Although it is not known whether such profound disparities in cell composition and association also exist in the PNS, it might as well be anticipated considering the many sophisticated sensory and motor activities that are unique to humans. Considerable species difference also manifest at a molecular level. […] At least 80% of human genes have a counterpart in the mouse and rat genome. However, temporal and spatial expression of these genes can vary remarkably between humans and rodents, in terms of both extent and isoform specificity.”

“Ultimately, a fundamental problem associated with resorting to rodents in DPN research is to study a human disorder that takes decades to develop and progress in organisms with a maximum lifespan of 2-3 years. […] It is […] fair to say that a full clinical spectrum of the maturity-onset DPN likely requires a length of time exceeding the longevity of rodents to present and diabetic rodent models at best only help illustrate the very early aspects of the entire disease syndrome. Since none of the early pathogenetic pathways revealed in diabetic rodents will contribute to DPN in a quantitatively and temporally uniform fashion throughout the prolonged natural history of this disease, it is not surprising that a handful of inhibitors developed against these processes have not benefited patients with relatively long-standing neuropathy. As a matter of fact, any agents targeting single biochemical insults would be too little too late to treat a chronic neurological disorder with established nerve damage and pathogenetic heterogeneity […] It is important to point out that the present review does not argue against the ability of animal models to shed light on basic molecular, cellular and physiological processes that are shared among species. Undoubtedly, animal models of diabetes have provided abundant insights into the disease biology of DPN. Nevertheless, the lack of any meaningful advance in identifying a promising pharmacological target necessitates a reexamination of the validity of current DPN models as well as to offer a plausible alternative methodology to scientific approaches and disease intervention. […] we conclude that the fundamental species differences have led to misinterpretation of rodent data and overall failure of pharmacological investment. As more is being learned, it is becoming prevailing that DPN is a chronic, heterogeneous disease unlikely to benefit from targeting specific and early pathogenetic components revealed by animal studies.”

February 13, 2018 Posted by | Books, Diabetes, Genetics, Medicine, Neurology, Pharmacology | Leave a comment

Endocrinology (part 4 – reproductive endocrinology)

Some observations from chapter 4 of the book below.

“*♂. The whole process of spermatogenesis takes approximately 74 days, followed by another 12-21 days for sperm transport through the epididymis. This means that events which may affect spermatogenesis may not be apparent for up to three months, and successful induction of spermatogenesis treatment may take 2 years. *♀. From primordial follicle to primary follicle, it takes about 180 days (a continuous process). It is then another 60 days to form a preantral follicle which then proceeds to ovulation three menstrual cycles later. Only the last 2-3 weeks of this process is under gonadotrophin drive, during which time the follicle grows from 2 to 20mm.”

“Hirsutism (not a diagnosis in itself) is the presence of excess hair growth in ♀ as a result of androgen production and skin sensitivity to androgens. […] In ♀, testosterone is secreted primarily by the ovaries and adrenal glands, although a significant amount is produced by the peripheral conversion of androstenedione and DHEA. Ovarian androgen production is regulated by luteinizing hormone, whereas adrenal production is ACTH-dependent. The predominant androgens produced by the ovaries are testosterone and androstenedione, and the adrenal glands are the main source of DHEA. Circulating testosterone is mainly bound to sex hormone-binding globulin (SHBG), and it is the free testosterone which is biologically active. […] Slowly progressive hirsutism following puberty suggests a benign cause, whereas rapidly progressive hirsutism of recent onset requires further immediate investigation to rule out an androgen-secreting neoplasm. [My italics, US] […] Serum testosterone should be measured in all ♀ presenting with hirsutism. If this is <5nmol/L, then the risk of a sinister cause for her hirsutism is low.”

“Polycystic ovary syndrome (PCOS) *A heterogeneous clinical syndrome characterized by hyperandrogenism, mainly of ovarian origin, menstrual irregularity, and hyperinsulinaemia, in which other causes of androgen excess have been excluded […] *A distinction is made between polycystic ovary morphology on ultrasound (PCO which also occurs in congenital adrenal hyperplasia, acromegaly, Cushing’s syndrome, and testesterone-secreting tumours) and PCOS – the syndrome. […] PCOS is the most common endocrinopathy in ♀ of reproductive age; >95% of ♀ presenting to outpatients with hirsutism have PCOS. *The estimated prevalence of PCOS ranges from 5 to 10% on clinical criteria. Polycystic ovaries on US alone are present in 20-25% of ♀ of reproductive age. […] family history of type 2 diabetes mellitus is […] more common in ♀ with PCOS. […] Approximately 70% of ♀ with PCOS are insulin-resistant, depending on the definition. […] Type 2 diabetes mellitus is 2-4 x more common in ♀ with PCOS. […] Hyperinsulinaemia is exacerbated by obesity but can also be present in lean ♀ with PCOS. […] Insulin […] inhibits SHBG synthesis by the liver, with a consequent rise in free androgen levels. […] Symptoms often begin around puberty, after weight gain, or after stopping the oral contraceptive pill […] Oligo-/amenorrhoea [is present in] 70% […] Hirsutism [is present in] 66% […] Obesity [is present in] 50% […] *Infertility (30%). PCOS accounts for 75% of cases of anovulatory infertility. The risk of spontaneous miscarriage is also thought to be higher than the general population, mainly because of obesity. […] The aims of investigations [of PCOS] are mainly to exclude serious underlying disorders and to screen for complications, as the diagnosis is primarily clinical […] Studies have uniformly shown that weight reduction in obese ♀ with PCOS will improve insulin sensitivity and significantly reduce hyperandrogenaemia. Obese ♀ are less likely to respond to antiandrogens and infertility treatment.”

“Androgen-secreting tumours [are] [r]are tumours of the ovary or adrenal gland which may be benign or malignant, which cause virilization in ♀ through androgen production. […] Virilization […] [i]ndicates severe hyperandrogenism, is associated with clitoromegaly, and is present in 98% of ♀ with androgen-producing tumours. Not usually a feature of PCOS. […] Androgen-secreting ovarian tumours[:] *75% develop before the age of 40 years. *Account for 0.4% of all ovarian tumours; 20% are malignant. *Tumours are 5-25cm in size. The larger they are, the more likely they are to be malignant. They are rarely bilateral. […] Androgen-secreting adrenal tumours[:] *50% develop before the age of 50 years. *Larger tumours […] are more likely to be malignant. *Usually with concomitant cortisol secretion as a variant of Cushing’s syndrome. […] Symptoms and signs of Cushing’s syndrome are present in many of ♀ with adrenal tumours. […] Onset of symptoms. Usually recent onset of rapidly progressive symptoms. […] Malignant ovarian and adrenal androgen-secreting tumours are usually resistant to chemotherapy and radiotherapy. […] *Adrenal tumours. 20% 5-year survival. Most have metastatic disease at the time of surgery. *Ovarian tumours. 30% disease-free survival and 40% overall survival at 5 years. […] Benign tumours. *Prognosis excellent. *Hirsutism improves post-operatively, but clitoromegaly, male pattern balding, and deep voice may persist.”

*Oligomenorrhoea is defined as the reduction in the frequency of menses to <9 periods a year. *1° amenorrhoea is the failure of menarche by the age of 16 years. Prevalence ~0.3% *2° amenorrhoea refers to the cessation of menses for >6 months in ♀ who had previously menstruated. Prevalence ~3%. […] Although the list of causes is long […], the majority of cases of secondary amenorrhoea can be accounted for by four conditions: *Polycystic ovary syndrome. *Hypothalamic amenorrhoea. *Hyperprolactinaemia. *Ovarian failure. […] PCOS is the only common endocrine cause of amenorrhoea with normal oestrogenization – all other causes are oestrogen-deficient. Women with PCOS, therefore, are at risk of endometrial hyperplasia, and all others are at risk of osteoporosis. […] Anosmia may indicate Kallman’s syndrome. […] In routine practice, a common differential diagnosis is between mild version of PCOS and hypothalamic amenorrhoea. The distinction between these conditions may require repeated testing, as a single snapshot may not discriminate. The reason to be precise is that PCOS is oestrogen-replete and will, therefore, respond to clomiphene citrate (an antioestrogen) for fertility. HA will be oestrogen-deficient and will need HRT and ovulation induction with pulsatile GnRH or hMG [human Menopausal Gonadotropins – US]. […] […] 75% of ♀ who develop 2° amenorrhoea report hot flushes, night sweats, mood changes, fatigue, or dyspareunia; symptoms may precede the onset of menstrual disturbances.”

“POI [Premature Ovarian Insufficiency] is a disorder characterized by amenorrhoea, oestrogen deficiency, and elevated gonadotrophins, developing in ♀ <40 years, as a result of loss of ovarian follicular function. […] *Incidence – 0.1% of ♀ <30 years and 1% of those <40 years. *Accounts for 10% of all cases of 2° amenorrhoea. […] POI is the result of accelerated depletion of ovarian germ cells. […] POI is usually permanent and progressive, although a remitting course is also experienced and cannot be fully predicted, so all women must know that pregnancy is possible, even though fertility treatments are not effective (often a difficult paradox to describe). Spontaneous pregnancy has been reported in 5%. […] 80% of [women with Turner’s syndrome] have POI. […] All ♀ presenting with hypergonadotrophic amenorrhoea below age 40 should be karyotyped.”

“The menopause is the permanent cessation of menstruation as a result of ovarian failure and is a retrospective diagnosis made after 12 months of amenorrhoea. The average age of at the time of the menopause is ~50 years, although smokers reach the menopause ~2 years earlier. […] Cycles gradually become increasingly anovulatory and variable in length (often shorter) from about 4 years prior to the menopause. Oligomenorrhoea often precedes permanent amenorrhoea. in 10% of ♀, menses cease abruptly, with no preceding transitional period. […] During the perimenopausal period, there is an accelerated loss of bone mineral density (BMD), rendering post-menopausal more susceptible to osteoporotic fractures. […] Post-menopausal are 2-3 x more likely to develop IHD [ischaemic heart disease] than premenopausal , even after age adjustments. The menopause is associated with an increase in risk factors for atherosclerosis, including less favourable lipid profile, insulin sensitivity, and an ↑ thrombotic tendency. […] ♀ are 2-3 x more likely to develop Alzheimer’s disease than ♂. It is suggested that oestrogen deficiency may play a role in the development of dementia. […] The aim of treatment of perimenopausal ♀ is to alleviate menopausal symptoms and optimize quality of life. The majority of women with mild symptoms require no HRT. […] There is an ↑ risk of breast cancer in HRT users which is related to the duration of use. The risk increases by 35%, following 5 years of use (over the age of 50), and falls to never-used risk 5 years after discontinuing HRT. For ♀ aged 50 not using HRT, about 45 in every 1,000 will have cancer diagnosed over the following 20 years. This number increases to 47/1,000 ♀ using HRT for 5 years, 51/1,000 using HRT for 10 years, and 57/1,000 after 15 years of use. The risk is highest in ♀ on combined HRT compared with oestradiol alone. […] Oral HRT increases the risk [of venous thromboembolism] approximately 3-fold, resulting in an extra two cases/10,000 women-years. This risk is markedly ↑ in ♀ who already have risk factors for DVT, including previous DVT, cardiovascular disease, and within 90 days of hospitalization. […] Data from >30 observational studies suggest that HRT may reduce the risk of developing CVD [cardiovascular disease] by up to 50%. However, randomized placebo-controlled trials […] have failed to show that HRT protects against IHD. Currently, HRT should not be prescribed to prevent cardiovascular disease.”

“Any chronic illness may affect testicular function, in particular chronic renal failure, liver cirrhosis, and haemochromatosis. […] 25% of  who develop mumps after puberty have associated orchitis, and 25-50% of these will develop 1° testicular failure. […] Alcohol excess will also cause 1° testicular failure. […] Cytotoxic drugs, particularly alkylating agents, are gonadotoxic. Infertility occurs in 50% of patients following chemotherapy, and a significant number of  require androgen replacement therapy because of low testosterone levels. […] Testosterone has direct anabolic effects on skeletal muscle and has been shown to increase muscle mass and strength when given to hypogonadal men. Lean body mass is also with a reduction in fat mass. […] Hypogonadism is a risk factor for osteoporosis. Testosterone inhibits bone resorption, thereby reducing bone turnover. Its administration to hypogonadal has been shown to improve bone mineral density and reduce the risk of developing osteoporosis. […] *Androgens stimulate prostatic growth, and testosterone replacement therapy may therefore induce symptoms of bladder outflow obstruction in with prostatic hypertrophy. *It is unlikely that testosterone increases the risk of developing prostrate cancer, but it may promote the growth of an existing cancer. […] Testosterone replacement therapy may cause a fall in both LDL and HDL cholesterol levels, the significance of which remains unclear. The effect of androgen replacement therapy on the risk of developing coronary artery disease is unknown.”

“Erectile dysfunction [is] [t]he consistent inability to achieve or maintain an erect penis sufficient for satisfactory sexual intercourse. Affects approximately 10% of and >50% of >70 years. […] Erectile dysfunction may […] occur as a result of several mechanisms: *Neurological damage. *Arterial insufficiency. *Venous incompetence. *Androgen deficiency. *Penile abnormalities. […] *Abrupt onset of erectile dysfunction which is intermittent is often psychogenic in origin. *Progressive and persistent dysfunction indicates an organic cause. […] Absence of morning erections suggests an organic cause of erectile dysfunction.”

“*Infertility, defined as failure of pregnancy after 1 year of unprotected regular (2 x week) sexual intercourse, affects ~10% of all couples. *Couples who fail to conceive after 1 years of regular unprotected sexual intercourse should be investigated. […] Causes[:] *♀ factors (e.g. PCOS, tubal damage) 35%. *♂ factors (idiopathic gonadal failure in 60%) 25%. *Combined factors 25%. *Unexplained infertility 15%. […] [♀] Fertility declines rapidly after the age of 36 years. […] Each episode of acute PID causes infertility in 10-15% of cases. *Trachomatis is responsible for half the cases of PID in developed countries. […] Unexplained infertility [is] [i]nfertility despite normal sexual intercourse occurring at least twice weakly, normal semen analysis, documentation of ovulation in several cycles, and normal patent tubes (by laparoscopy). […] 30-50% will become pregnant within 3 years of expectant management. If not pregnant by then, chances that spontaneous pregnancy will occur are greatly reduced, and ART should be considered. In ♀>34 years of age, then expectant management is not an option, and up to six cycles of IUI or IVF should be considered.”

February 9, 2018 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Genetics, Medicine, Pharmacology | Leave a comment

Systems Biology (I)

This book is really dense and is somewhat tough for me to blog. One significant problem is that: “The authors assume that the reader is already familiar with the material covered in a classic biochemistry course.” I know enough biochem to follow most of the stuff in this book, and I was definitely quite happy to have recently read John Finney’s book on the biochemical properties of water and Christopher Hall’s introduction to materials science, as both of those books’ coverage turned out to be highly relevant (these are far from the only relevant books I’ve read semi-recently – Atkins introduction to thermodynamics is another book that springs to mind) – but even so, what do you leave out when writing a post like this? I decided to leave out a lot. Posts covering books like this one are hard to write because it’s so easy for them to blow up in your face because you have to include so many details for the material included in the post to even start to make sense to people who didn’t read the original text. And if you leave out all the details, what’s really left? It’s difficult..

Anyway, some observations from the first chapters of the book below.

“[T]he biological world consists of self-managing and self-organizing systems which owe their existence to a steady supply of energy and information. Thermodynamics introduces a distinction between open and closed systems. Reversible processes occurring in closed systems (i.e. independent of their environment) automatically gravitate toward a state of equilibrium which is reached once the velocity of a given reaction in both directions becomes equal. When this balance is achieved, we can say that the reaction has effectively ceased. In a living cell, a similar condition occurs upon death. Life relies on certain spontaneous processes acting to unbalance the equilibrium. Such processes can only take place when substrates and products of reactions are traded with the environment, i.e. they are only possible in open systems. In turn, achieving a stable level of activity in an open system calls for regulatory mechanisms. When the reaction consumes or produces resources that are exchanged with the outside world at an uneven rate, the stability criterion can only be satisfied via a negative feedback loop […] cells and living organisms are thermodynamically open systems […] all structures which play a role in balanced biological activity may be treated as components of a feedback loop. This observation enables us to link and integrate seemingly unrelated biological processes. […] the biological structures most directly involved in the functions and mechanisms of life can be divided into receptors, effectors, information conduits and elements subject to regulation (reaction products and action results). Exchanging these elements with the environment requires an inflow of energy. Thus, living cells are — by their nature — open systems, requiring an energy source […] A thermodynamically open system lacking equilibrium due to a steady inflow of energy in the presence of automatic regulation is […] a good theoretical model of a living organism. […] Pursuing growth and adapting to changing environmental conditions calls for specialization which comes at the expense of reduced universality. A specialized cell is no longer self-sufficient. As a consequence, a need for higher forms of intercellular organization emerges. The structure which provides cells with suitable protection and ensures continued homeostasis is called an organism.”

“In biology, structure and function are tightly interwoven. This phenomenon is closely associated with the principles of evolution. Evolutionary development has produced structures which enable organisms to develop and maintain its architecture, perform actions and store the resources needed to survive. For this reason we introduce a distinction between support structures (which are akin to construction materials), function-related structures (fulfilling the role of tools and machines), and storage structures (needed to store important substances, achieving a compromise between tight packing and ease of access). […] Biology makes extensive use of small-molecule structures and polymers. The physical properties of polymer chains make them a key building block in biological structures. There are several reasons as to why polymers are indispensable in nature […] Sequestration of resources is subject to two seemingly contradictory criteria: 1. Maximize storage density; 2. Perform sequestration in such a way as to allow easy access to resources. […] In most biological systems, storage applies to energy and information. Other types of resources are only occasionally stored […]. Energy is stored primarily in the form of saccharides and lipids. Saccharides are derivatives of glucose, rendered insoluble (and thus easy to store) via polymerization.Their polymerized forms, stabilized with α-glycosidic bonds, include glycogen (in animals) and starch (in plantlife). […] It should be noted that the somewhat loose packing of polysaccharides […] makes them unsuitable for storing large amounts of energy. In a typical human organism only ca. 600 kcal of energy is stored in the form of glycogen, while (under normal conditions) more than 100,000 kcal exists as lipids. Lipids deposit usually assume the form of triglycerides (triacylglycerols). Their properties can be traced to the similarities between fatty acids and hydrocarbons. Storage efficiency (i.e. the amount of energy stored per unit of mass) is twice that of polysaccharides, while access remains adequate owing to the relatively large surface area and high volume of lipids in the organism.”

“Most living organisms store information in the form of tightly-packed DNA strands. […] It should be noted that only a small percentage of DNA (about few %) conveys biologically relevant information. The purpose of the remaining ballast is to enable suitable packing and exposure of these important fragments. If all of DNA were to consist of useful code, it would be nearly impossible to devise a packing strategy guaranteeing access to all of the stored information.”

“The seemingly endless diversity of biological functions frustrates all but the most persistent attempts at classification. For the purpose of this handbook we assume that each function can be associated either with a single cell or with a living organism. In both cases, biological functions are strictly subordinate to automatic regulation, based — in a stable state — on negative feedback loops, and in processes associated with change (for instance in embryonic development) — on automatic execution of predetermined biological programs. Individual components of a cell cannot perform regulatory functions on their own […]. Thus, each element involved in the biological activity of a cell or organism must necessarily participate in a regulatory loop based on processing information.”

“Proteins are among the most basic active biological structures. Most of the well-known proteins studied thus far perform effector functions: this group includes enzymes, transport proteins, certain immune system components (complement factors) and myofibrils. Their purpose is to maintain biological systems in a steady state. Our knowledge of receptor structures is somewhat poorer […] Simple structures, including individual enzymes and components of multienzyme systems, can be treated as “tools” available to the cell, while advanced systems, consisting of many mechanically-linked tools, resemble machines. […] Machinelike mechanisms are readily encountered in living cells. A classic example is fatty acid synthesis, performed by dedicated machines called synthases. […] Multiunit structures acting as machines can be encountered wherever complex biochemical processes need to be performed in an efficient manner. […] If the purpose of a machine is to generate motion then a thermally powered machine can accurately be called a motor. This type of action is observed e.g. in myocytes, where transmission involves reordering of protein structures using the energy generated by hydrolysis of high-energy bonds.”

“In biology, function is generally understood as specific physiochemical action, almost universally mediated by proteins. Most such actions are reversible which means that a single protein molecule may perform its function many times. […] Since spontaneous noncovalent surface interactions are very infrequent, the shape and structure of active sites — with high concentrations of hydrophobic residues — makes them the preferred area of interaction between functional proteins and their ligands. They alone provide the appropriate conditions for the formation of hydrogen bonds; moreover, their structure may determine the specific nature of interaction. The functional bond between a protein and a ligand is usually noncovalent and therefore reversible.”

“In general terms, we can state that enzymes accelerate reactions by lowering activation energies for processes which would otherwise occur very slowly or not at all. […] The activity of enzymes goes beyond synthesizing a specific protein-ligand complex (as in the case of antibodies or receptors) and involves an independent catalytic attack on a selected bond within the ligand, precipitating its conversion into the final product. The relative independence of both processes (binding of the ligand in the active site and catalysis) is evidenced by the phenomenon of noncompetitive inhibition […] Kinetic studies of enzymes have provided valuable insight into the properties of enzymatic inhibitors — an important field of study in medicine and drug research. Some inhibitors, particularly competitive ones (i.e. inhibitors which outcompete substrates for access to the enzyme), are now commonly used as drugs. […] Physical and chemical processes may only occur spontaneously if they generate energy, or non-spontaneously if they consume it. However, all processes occurring in a cell must have a spontaneous character because only these processes may be catalyzed by enzymes. Enzymes merely accelerate reactions; they do not provide energy. […] The change in enthalpy associated with a chemical process may be calculated as a net difference in the sum of molecular binding energies prior to and following the reaction. Entropy is a measure of the likelihood that a physical system will enter a given state. Since chaotic distribution of elements is considered the most probable, physical systems exhibit a general tendency to gravitate towards chaos. Any form of ordering is thermodynamically disadvantageous.”

“The chemical reactions which power biological processes are characterized by varying degrees of efficiency. In general, they tend to be on the lower end of the efficiency spectrum, compared to energy sources which drive matter transformation processes in our universe. In search for a common criterion to describe the efficiency of various energy sources, we can refer to the net loss of mass associated with a release of energy, according to Einstein’s formula:
E = mc2
M/M coefficient (relative loss of mass, given e.g. in %) allows us to compare the efficiency of energy sources. The most efficient processes are those involved in the gravitational collapse of stars. Their efficiency may reach 40 %, which means that 40 % of the stationary mass of the system is converted into energy. In comparison, nuclear reactions have an approximate efficiency of 0.8 %. The efficiency of chemical energy sources available to biological systems is incomparably lower and amounts to approximately 10(-7) % […]. Among chemical reactions, the most potent sources of energy are found in oxidation processes, commonly exploited by biological systems. Oxidation tends  to result in the largest net release of energy per unit of mass, although the efficiency of specific types of oxidation varies. […] given unrestricted access to atmospheric oxygen and to hydrogen atoms derived from hydrocarbons — the combustion of hydrogen (i.e. the synthesis of water; H2 + 1/2O2 = H2O) has become a principal source of energy in nature, next to photosynthesis, which exploits the energy of solar radiation. […] The basic process associated with the release of hydrogen and its subsequent oxidation (called the Krebs cycle) is carried by processes which transfer electrons onto oxygen atoms […]. Oxidation occurs in stages, enabling optimal use of the released energy. An important byproduct of water synthesis is the universal energy carrier known as ATP (synthesized separately). As water synthesis is a highly spontaneous process, it can be exploited to cover the energy debt incurred by endergonic synthesis of ATP, as long as both processes are thermodynamically coupled, enabling spontaneous catalysis of anhydride bonds in ATP. Water synthesis is a universal source of energy in heterotrophic systems. In contrast, autotrophic organisms rely on the energy of light which is exploited in the process of photosynthesis. Both processes yield ATP […] Preparing nutrients (hydrogen carriers) for participation in water synthesis follows different paths for sugars, lipids and proteins. This is perhaps obvious given their relative structural differences; however, in all cases the final form, which acts as a substrate for dehydrogenases, is acetyl-CoA“.

“Photosynthesis is a process which — from the point of view of electron transfer — can be treated as a counterpart of the respiratory chain. In heterotrophic organisms, mitochondria transport electrons from hydrogenated compounds (sugars, lipids, proteins) onto oxygen molecules, synthesizing water in the process, whereas in the course of photosynthesis electrons released by breaking down water molecules are used as a means of reducing oxydised carbon compounds […]. In heterotrophic organisms the respiratory chain has a spontaneous quality (owing to its oxidative properties); however any reverse process requires energy to occur. In the case of photosynthesis this energy is provided by sunlight […] Hydrogen combustion and photosynthesis are the basic sources of energy in the living world. […] For an energy source to become useful, non-spontaneous reactions must be coupled to its operation, resulting in a thermodynamically unified system. Such coupling can be achieved by creating a coherent framework in which the spontaneous and non-spontaneous processes are linked, either physically or chemically, using a bridging component which affects them both. If the properties of both reactions are different, the bridging component must also enable suitable adaptation and mediation. […] Direct exploitation of the energy released via the hydrolysis of ATP is possible usually by introducing an active binding carrier mediating the energy transfer. […] Carriers are considered active as long as their concentration ensures a sufficient release of energy to synthesize a new chemical bond by way of a non-spontaneous process. Active carriers are relatively short-lived […] Any active carrier which performs its function outside of the active site must be sufficiently stable to avoid breaking up prior to participating in the synthesis reaction. Such mobile carriers are usually produced when the required synthesis consists of several stages or cannot be conducted in the active site of the enzyme for sterical reasons. Contrary to ATP, active energy carriers are usually reaction-specific. […] Mobile energy carriers are usually formed as a result of hydrolysis of two high-energy ATP bonds. In many cases this is the minimum amount of energy required to power a reaction which synthesizes a single chemical bond. […] Expelling a mobile or unstable reaction component in order to increase the spontaneity of active energy carrier synthesis is a process which occurs in many biological mechanisms […] The action of active energy carriers may be compared to a ball rolling down a hill. The descending snowball gains sufficient energy to traverse another, smaller mound, adjacent to its starting point. In our case, the smaller hill represents the final synthesis reaction […] Understanding the role of active carriers is essential for the study of metabolic processes.”

“A second category of processes, directly dependent on energy sources, involves structural reconfiguration of proteins, which can be further differentiated into low and high-energy reconfiguration. Low-energy reconfiguration occurs in proteins which form weak, easily reversible bonds with ligands. In such cases, structural changes are powered by the energy released in the creation of the complex. […] Important low-energy reconfiguration processes may occur in proteins which consist of subunits. Structural changes resulting from relative motion of subunits typically do not involve significant expenditures of energy. Of particular note are the so-called allosteric proteins […] whose rearrangement is driven by a weak and reversible bond between the protein and an oxygen molecule. Allosteric proteins are genetically conditioned to possess two stable structural configurations, easily swapped as a result of binding or releasing ligands. Thus, they tend to have two comparable energy minima (separated by a low threshold), each of which may be treated as a global minimum corresponding to the native form of the protein. Given such properties, even a weakly interacting ligand may trigger significant structural reconfiguration. This phenomenon is of critical importance to a variety of regulatory proteins. In many cases, however, the second potential minimum in which the protein may achieve relative stability is separated from the global minimum by a high threshold requiring a significant expenditure of energy to overcome. […] Contrary to low-energy reconfigurations, the relative difference in ligand concentrations is insufficient to cover the cost of a difficult structural change. Such processes are therefore coupled to highly exergonic reactions such as ATP hydrolysis. […]  The link between a biological process and an energy source does not have to be immediate. Indirect coupling occurs when the process is driven by relative changes in the concentration of reaction components. […] In general, high-energy reconfigurations exploit direct coupling mechanisms while indirect coupling is more typical of low-energy processes”.

Muscle action requires a major expenditure of energy. There is a nonlinear dependence between the degree of physical exertion and the corresponding energy requirements. […] Training may improve the power and endurance of muscle tissue. Muscle fibers subjected to regular exertion may improve their glycogen storage capacity, ATP production rate, oxidative metabolism and the use of fatty acids as fuel.

February 4, 2018 Posted by | Biology, Books, Chemistry, Genetics, Pharmacology, Physics | Leave a comment

Endocrinology (part 3 – adrenal glands)

Some observations from chapter 3 below.

“The normal adrenal gland weigh 4-5g. The cortex represents 90% of the normal gland and surrounds the medulla. […] Glucocorticoid (cortisol […]) production occurs from the zona fasciculata, and adrenal androgens arise from the zona reticularis. Both of these are under the control of ACTH [see also my previous post about the book – US], which regulates both steroid synthesis and also adrenocortical growth. […] Mineralocorticoid (aldosterone […]) synthesis occurs in zona glomerulosa, predominantly under the control of the renin-angiotensin system […], although ACTH also contributes to its regulation. […] The adrenal gland […] also produces sex steroids in the form of dehydroepiandrostenedione (DHEA) and androstenedione. The synthetic pathway is under the control of ACTH. Urinary steroid profiling provides quantitative information on the biosynthetic and catabolic pathways. […] CT is the most widely used modality for imaging the adrenal glands. […] MRI can also reliably detect adrenal masses >5-10mm in diameter and, in some circumstances, provides additional information to CT […] PET can be useful in locating tumours and metastases. […] Adrenal vein sampling (AVS) […] can be useful to lateralize an adenoma or to differentiate an adenoma from bilateral hyperplasia. […] AVS is of particular value in lateralizing small aldosterone-producing adenomas that cannot easily be visualized on CT or MRI. […] The procedure should only be undertaken in patients in whom surgery is feasible and desired […] [and] should be carried out in specialist centres only; centres with <20 procedures per year have been shown to have poor success rates”.

“The majority of cases of mineralocorticoid excess are due to excess aldosterone production, […] typically associated with hypertension and hypokalemia. *Primary hyperaldosteronism is a disorder of autonomous aldosterone hypersecretion with suppressed renin levels. *Secondary hyperaldosteronism occurs when aldosterone hypersecretion occurs 2° [secondary, US] to elevated circulating renin levels. This is typical of heart failure, cirrhosis, or nephrotic syndrome but can also be due to renal artery stenosis and, occasionally, a very rare renin-producing tumour (reninoma). […] Primary hyperaldosteronism is present in around 10% of hypertensive patients. It is the most prevalent form of secondary hypertension. […] Aldosterone causes renal sodium retention and potassium loss. This results in expansion of body sodium content, leading to suppression of renal renin synthesis. The direct action of aldosterone on the distal nephron causes sodium retention and loss and hydrogen and potassium ions, resulting in a hypokalaemic alkalosis, although serum potassium […] may be normal in up to 50% of cases. Aldosterone has pathophysiological effects on a range of other tissues, causing cardiac fibrosis, vascular endothelial dysfunction, and nephrosclerosis. […] hypertension […] is often resistant to conventional therapy. […] Hypokalaemia is usually asymptomatic. […] Occasionally, the clinical syndrome of hyperaldosteronism is not associated with excess aldosterone. […] These conditions are rare.”

“Bilateral adrenal hyperplasia [make up] 60% [of cases of primary hyperaldosteronism]. […] Conn’s syndrome (aldosterone-producing adrenal adenoma) [make up] 35%. […] The pathophysiology of bilateral adrenal hyperplasia is not understood, and it is possible that it represents an extreme end of the spectrum of low renin essential hypertension. […] Aldosterone-producing carcinoma[s] [are] [r]are and usually associated with excessive secretion of other corticosteroids (cortisol, androgen, oestrogen). […] Indications [for screening include:] *Patients resistant to conventional antihypertensive medication (i.e. not controlled on three agents). *Hypertension associated with hypokalaemia […] *Hypertension developing before age of 40 years. […] Confirmation of autonomous aldosterone production is made by demonstrating failure to suppress aldosterone in face of sodium/volume loading. […] A number of tests have been described that are said to differentiate between the various subtypes of 1° [primary, US] aldosteronism […]. However, none of these are sufficiently specific to influence management decisions”.

“Laparoscopic adrenalectomy is the treatment of choice for aldosterone-secreting adenomas […] and laparoscopic adrenalectomy […] has become the procedure of choice for removal of most adrenal tumours. *Hypertension is cured in about 70%. *If it persists […], it is more amenable to medical treatment. *Overall, 50% become normotensive in 1 month and 70% within 1 year. […] Medical therapy remains an option for patients with bilateral disease and those with a solitary adrenal adenoma who are unlikely to be cured by surgery, who are unfit for operation, or who express a preference for medical management. *The mineralocorticoid receptor antagonist spironolactone […] has been used successfully for many years to treat hypertension and hypokalaemia associated with bilateral adrenal hyperplasia […] Side effects are common – particularly gynaecomastia and impotence in ♂, menstrual irregularities in ♀, and GI effects. […] Eplerenone […] is a mineralocorticoid receptor antagonist without antiandrogen effects and hence greater selectivity and less side effects than spironolactone. *Alternative drugs include the potassium-sparing diuretics amiloride and triamterene.”

“Cushing’s syndrome results from chronic excess cortisol [see also my second post in this series] […] The causes may be classified as ACTH-dependent and ACTH-independent. […] ACTH-independent Cushing’s syndrome […] is due to adrenal tumours (benign and malignant), and is responsible for 10-15% of cases of Cushing’s syndrome. […] Benign adrenocortical adenomas (ACA) are usually encapsulated and <4cm in diameter. They are usually associated with pure glucocorticoid excess. *Adrenocortical carcinomas (ACC) are usually >6cm in diameter, […] and are not infrequently associated with local invasion and metastases at the time of diagnosis. Adrenal carcinomas are characteristically associated with the excess secretion of several hormones; most frequently found is the combination of cortisol and androgen (precursors) […] ACTH-dependent Cushing’s results in bilateral adrenal hyperplasia, thus one has to firmly differentiate between ACTH-dependent and independent causes of Cushing’s before assuming bilateral adrenal hyperplasia as the primary cause of disease. […] It is important to note that, in patients with adrenal carcinoma, there may also be features related to excessive androgen production in ♀ and also a relatively more rapid time course of development of the syndrome. […] Patients with ACTH-independent Cushing’s syndrome do not suppress cortisol […] on high-dose dexamethasone testing and fail to show a rise in cortisol and ACTH following administration of CRH. […] ACTH-independent causes are adrenal in origin, and the mainstay of further investigation is adrenal imaging by CT”.

“Adrenal adenomas, which are successfully treated with surgery, have a good prognosis, and recurrence is unlikely. […] Bilateral adrenalectomy [in the context of bilateral adrenal hyperplasia] is curative. Lifelong glucocorticoid and mineralocorticoid treatment is [however] required. […] The prognosis for adrenal carcinoma is very poor despite surgery. Reports suggest a 5-year survival of 22% and median survival time of 14 months […] Treatment of adrenocortical carcinoma (ACC) should be carried out in a specialist centre, with expert surgeons, oncologists, and endocrinologists with extensive treatment in treating ACC. This improves survival.”

“Adrenal insufficiency [AI, US] is defined by the lack of cortisol, i.e. glucocorticoid deficiency, may be due to destruction of the adrenal cortex (1°, Addison’s disease and congenital adrenal hyperplasia (CAH) […] or due to disordered pituitary and hypothalamic function (2°). […] *Permanent adrenal insufficiency is found in 5 in 10,000 population. *The most frequent cause is hypothalamic-pituitary damage, which is the cause of AI in 60% of affected patients. *The remaining 40% of cases are due to primary failure of the adrenal to synthesize cortisol, almost equal prevalence of Addison’s disease (mostly of autoimmune origin, prevalence 0.9-1.4 in 10,000) and congenital adrenal hyperplasia (0.7-1.0 in 10,000). *2° adrenal insufficiency due to suppression of pituitary-hypothalamic function by exogenously administered, supraphysiological glucocorticoid doses for treatment of, for example, COPD or rheumatoid arthritis, is much more common (50-200 in 10,000 population). However, adrenal function in these patients can recover”.

“[In primary AI] [a]drenal gland destruction or dysfunction occurs due to a disease process which usually involves all three zones of the adrenal cortex, resulting in inadequate glucocorticoid, mineralocorticoid, and adrenal androgen precursor secretion. The manifestations of insufficiency do not usually appear until at least 90% of the gland has been destroyed and are usually gradual in onset […] Acute adrenal insufficiency may occur in the context of acute septicaemia […] Mineralocorticoid deficiency leads to reduced sodium retention and hyponatraemia and hypotension […] Androgen deficiency presents in ♀ with reduced axillary and pubic hair and reduced libido. (Testicular production of androgens is more important in ♂). [In secondary AI] [i]nadequate ACTH results in deficient cortisol production (and ↓ androgens in ♀). […] Mineralocorticoid secretion remains normal […] The onset is usually gradual, with partial ACTH deficiency resulting in reduced response to stress. […] Lack of stimulation of skin MC1R due to ACTH deficiency results in pale skin appearance. […] [In 1° adrenal insufficiency] hyponatraemia is present in 90% and hyperkalaemia in 65%. […] Undetectable serum cortisol is diagnostic […], but the basal cortisol is often in the normal range. A cortisol >550nmol/L precludes the diagnosis. At times of acute stress, an inappropriately low cortisol is very suggestive of the diagnosis.”

“Autoimmune adrenalitis[:] Clinical features[:] *Anorexia and weight loss (>90%). *Tiredness. *Weakness – generalized, no particular muscle groups. […] Dizziness and postural hypotension. *GI symptoms – nausea and vomiting, abdominal pain, diarrhea. *Arthralgia and myalgia. […] *Mediated by humoral and cell-mediated immune mechanisms. Autoimmune insufficiency associated with polyglandular autoimmune syndrome is more common in ♀ (70%). *Adrenal cortex antibodies are present in the majority of patients at diagnosis, and […] they are still found in approximately 70% of patients 10 years later. Up to 20% patients/year with [positive] antibodies develop adrenal insufficiency. […] *Antiadrenal antibodies are found in <2% of patients with other autoimmune endocrine disease (Hashimoto’s thyroiditis, diabetes mellitus, autoimmune hypothyroidism, hypoparathyroidism, pernicious anemia). […] antibodies to other endocrine glands are commonly found in patients with autoimmune adrenal insufficiency […] However, the presence of antibodies does not predict subsequent manifestation of organ-specific autoimmunity. […] Patients with type 1 diabetes mellitus and autoimmune thyroid disease only rarely develop autoimmune adrenal insufficiency. Approximately 60% of patients with Addison’s disease have other autoimmune or endocrine disorders. […] The adrenals are small and atrophic in chronic autoimmune adrenalitis.”

“Autoimmune polyglandular syndrome (APS) type 1[:] *Also known as autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED). […] [C]hildhood onset. *Chronic mucocutaneous candidiasis. *Hypoparathyroidism (90%), 1° adrenal insufficiency (60%). *1° gonadal failure (41%) – usually after Addison’s diagnosis. *1° hypothyroidism. *Rarely hypopituitarism, diabetes insipidus, type 1 diabetes mellitus. […] APS type 2[:] *Adult onset. *Adrenal insufficiency (100%). 1° autoimmune thyroid disease (70%) […] Type 1 diabetes mellitus (5-20%) – often before Addison’s diagnosis. *1° gonadal failure in affected women (5-20%). […] Schmidt’s syndrome: *Addison’s disease, and *Autoimmune hypothyroidism. *Carpenter syndrome: *Addison’s disease, and *Autoimmune hypothyroidism, and/or *Type 1 diabetes mellitus.”

“An adrenal incidentaloma is an adrenal mass that is discovered incidentally upon imaging […] carried out for reasons other than a suspected adrenal pathology.  […] *Autopsy studies suggest incidence prevalence of adrenal masses of 1-6% in the general population. *Imagining studies suggest that adrenal masses are present 2-3% in the general population. Incidence increases with ageing, and 8-10% of 70-year olds harbour an adrenal mass. […] It is important to determine whether the incidentally discovered adrenal mass is: *Malignant. *Functioning and associated with excess hormonal secretion.”

January 17, 2018 Posted by | Books, Cancer/oncology, Diabetes, Epidemiology, Immunology, Medicine, Nephrology, Pharmacology | Leave a comment

Endocrinology (part 2 – pituitary)

Below I have added some observations from the second chapter of the book, which covers the pituitary gland.

“The pituitary gland is centrally located at the base of the brain in the sella turcica within the sphenoid bone. It is attached to the hypothalamus by the pituitary stalk and a fine vascular network. […] The pituitary measures around 13mm transversely, 9mm anteroposteriorly, and 6mm vertically and weighs approximately 100mg. It increases during pregnancy to almost twice its normal size, and it decreases in the elderly. *Magnetic resonance imaging (MRI) currently provides the optimal imaging of the pituitary gland. *Computed tomography (CT) scans may still be useful in demonstrating calcification in tumours […] and hyperostosis in association with meningiomas or evidence of bone destruction. […] T1– weighted images demonstrate cerebrospinal fluid (CSF) as dark grey and brain as much whiter. This imagining is useful for demonstrating anatomy clearly. […] On T1– weighted images, pituitary adenomas are of lower signal intensity than the remainder of the normal gland. […] The presence of microadenomas may be difficult to demonstrate.”

“Hypopituitarism refers to either partial or complete deficiency of anterior and/or posterior pituitary hormones and may be due to [primary] pituitary disease or to hypothalamic pathology which interferes with the hypothalamic control of the pituitary. Causes: *Pituitary tumours. *Parapituitary tumours […] *Radiotherapy […] *Pituitary infarction (apoplexy), Sheehan’s syndrome. *Infiltration of the pituitary gland […] *infection […] *Trauma […] *Subarachnoid haemorrhage. *Isolated hypothalamic-releasing hormone deficiency, e.g. Kallmann’s syndrome […] *Genetic causes [Let’s stop here: Point is, lots of things can cause pituitary problems…] […] The clinical features depend on the type and degree of hormonal deficits, and the rate of its development, in addition to whether there is intercurrent illness. In the majority of cases, the development of hypopituitarism follows a characteristic order, which secretion of GH [growth hormone, US], then gonadotrophins being affected first, followed by TSH [Thyroid-Stimulating Hormone, US] and ACTH [Adrenocorticotropic Hormone, US] secretion at a later stage. PRL [prolactin, US] deficiency is rare, except in Sheehan’s syndrome associated with failure of lactation. ADH [antidiuretic hormone, US] deficiency is virtually unheard of with pituitary adenomas but may be seen rarely with infiltrative disorders and trauma. The majority of the clinical features are similar to those occurring when there is target gland insufficiency. […] NB Houssay phenomenon. Amelioration of diabetes mellitus in patients with hypopituitarism due to reduction in counter-regulatory hormones. […] The aims of investigation of hypopituitarism are to biochemically assess the extent of pituitary hormone deficiency and also to elucidate the cause. […] Treatment involves adequate and appropriate hormone replacement […] and management of the underlying cause.”

“Apoplexy refers to infarction of the pituitary gland due to either haemorrhage or ischaemia. It occurs most commonly in patients with pituitary adenomas, usually macroadenomas […] It is a medical emergency, and rapid hydrocortisone replacement can be lifesaving. It may present with […] sudden onset headache, vomiting, meningism, visual disturbance, and cranial nerve palsy.”

“Anterior pituitary hormone replacement therapy is usually performed by replacing the target hormone rather than the pituitary or hypothalamic hormone that is actually deficient. The exceptions to this are GH replacement […] and when fertility is desired […] [In the context of thyroid hormone replacement:] In contrast to replacement in [primary] hypothyroidism, the measurement of TSH cannot be used to assess adequacy of replacment in TSH deficiency due to hypothalamo-pituitary disease. Therefore, monitoring of treatment in order to avoid under- and over-replacement should be via both clinical assessment and by measuring free thyroid hormone concentrations […] [In the context of sex hormone replacement:] Oestrogen/testosterone administration is the usual method of replacement, but gonadotrophin therapy is required if fertility is desired […] Patients with ACTH deficiency usually need glucocorticoid replacement only and do not require mineralcorticoids, in contrast to patients with Addison’s disease. […] Monitoring of replacement [is] important to avoid over-replacement which is associated with BP, elevated glucose and insulin, and reduced bone mineral density (BMD). Under-replacement leads to the non-specific symptoms, as seen in Addison’s disease […] Conventional replacement […] may overtreat patients with partial ACTH deficiency.”

“There is now a considerable amount of evidence that there are significant and specific consequences of GH deficiency (GDH) in adults and that many of these features improve with GH replacement therapy. […] It is important to differentiate between adult and childhood onset GDH. […] the commonest cause in childhood is an isolated variable deficiency of GH-releasing hormone (GHRH) which may resolve in adult life […] It is, therefore, important to retest patients with childhood onset GHD when linear growth is completed (50% recovery of this group). Adult onset. GHD usually occurs [secondarily] to a structural pituitary or parapituitary condition or due to the effects of surgical treatment or radiotherapy. Prevalence[:] *Adult onset GHD 1/10,000 *Adult GHD due to adult and childhood onset GHD 3/10,000. Benefits of GH replacement[:] *Improved QoL and psychological well-being. *Improved exercise capacity. *↑ lean body mass and reduced fat mass. *Prolonged GH replacement therapy (>12-24 months) has been shown to increase BMD, which would be expected to reduce fracture rate. *There are, as yet, no outcome studies in terms of cardiovascular mortality. However, GH replacement does lead to a reduction (~15%) in cholesterol. GH replacement also leads to improved ventricular function and ↑ left ventricular mass. […] All patients with GHD should be considered for GH replacement therapy. […] adverse effects experienced with GH replacement usually resolve with dose reduction […] GH treatment may be associated with impairment of insulin sensitivity, and therefore markers of glycemia should be monitored. […] Contraindications to GH replacement[:] *Active malignancy. *Benign intracranial hypertension. *Pre-proliferative/proliferative retinopathy in diabetes mellitus.”

“*Pituitary adenomas are the most common pituitary disease in adults and constitute 10-15% of primary brain tumours. […] *The incidence of clinically apparent pituitary disease is 1 in 10,000. *Pituitary carcinoma is very rare (<0.1% of all tumours) and is most commonly ACTH- or prolactin-secreting. […] *Microadenoma <1cm. *Macroadenoma >1cm. [In terms of the functional status of tumours, the break-down is as follows:] *Prolactinoma 35-40%. *Non-functioning 30-35%. Growth hormone (acromegaly) 10-15%. *ACTH adenoma (Cushing’s disease) 5-10% *TSH adenoma <5%. […] Pituitary disease is associated with an increased mortality, predominantly due to vascular disease. This may be due to oversecretion of GH or ACTH, hormone deficiencies or excessive replacement (e.g. of hydrocortisone).”

“*Prolactinomas are the commonest functioning pituitary tumour. […] Malignant prolactinomas are very rare […] [Clinical features of hyperprolactinaemia:] *Galactorrhoea (up to 90%♀, <10% ♂). *Disturbed gonadal function [menstrual disturbance, infertility, reduced libido, ED in ♂] […] Hyperprolactinaemia is associated with a long-term risk of BMD. […] Hypothyroidism and chronic renal failure are causes of hyperprolactinaemia. […] Antipsychotic agents are the most likely psychotrophic agents to cause hyperprolactinaemia. […] Macroadenomas are space-occupying tumours, often associated with bony erosion and/or cavernous sinus invasion. […] *Invasion of the cavernous sinus may lead to cranial nerve palsies. *Occasionally, very invasive tumours may erode bone and present with a CSF leak or [secondary] meningitis. […] Although microprolactinomas may expand in size without treatment, the vast majority do not. […] Macroprolactinomas, however, will continue to expand and lead to pressure effects. Definite treatment of the tumour is, therefore, necessary.”

“Dopamine agonist treatment […] leads to suppression of PRL in most patients [with prolactinoma], with [secondary] effects of normalization of gonadal function and termination of galactorrhoea. Tumour shrinkage occurs at a variable rate (from 24h to 6-12 months) and extent and must be carefully monitored. Continued shrinkage may occur for years. Slow chiasmal decompression will correct visual field defects in the majority of patients, and immediate surgical decompression is not necessary. […] Cabergoline is more effective in normalization of PRL in microprolactinoma […], with fewer side effects than bromocriptine. […] Tumour enlargement following initial shrinkage on treatment is usually due to non-compliance. […] Since the introduction of dopamine agonist treatment, transsphenoidal surgery is indicated only for patients who are resistant to, or intolerant of, dopamine agonist treatment. The cure rate for macroprolactinomas treated with surgery is poor (30%), and, therefore, drug treatment is first-line in tumours of all size. […] Standard pituitary irradiation leads to slow reduction (over years) of PRL in the majority of patients. […] Radiotherapy is not indicated in the management of patients with microprolactinomas. It is useful in the treatment of macroprolactinomas once the tumour has been shrunken away from the chiasm, only if the tumour is resistant.”

“Acromegaly is the clinical condition resulting from prolonged excessive GH and hence IGF-1 secretion in adults. GH secretion is characterized by blunting of pulsatile secretion and failure of GH to become undetectable during the 24h day, unlike normal controls. […] *Prevalence 40-86 cases/million population. Annual incidence of new cases in the UK is 4/million population. *Onset is insidious, and there is, therefore, often a considerable delay between onset of clinical features and diagnosis. Most cases are diagnosed at 40-60 years. […] Pituitary gigantism [is] [t]he clinical syndrome resulting from excess GH secretion in children prior to fusion of the epiphyses. […] growth velocity without premature pubertal manifestations should arouse suspicion of pituitary gigantism. […] Causes of acromegaly[:] *Pituitary adenoma (>99% of cases). Macroadenomas 60-80%, microadenomas 20-40%. […] The clinical features arise from the effects of excess GH/IGF-1, excess PRL in some (as there is co-secretion of PRL in a minority (30%) of tumours […] and the tumour mass. [Signs and symptoms:] * sweating -> 80% of patients. *Headaches […] *Tiredness and lethargy. *Joint pains. *Change in ring or shoe size. *Facial appearance. Coarse features […] enlarged nose […] prognathism […] interdental separation. […] Enlargement of hands and feet […] [Complications:] *Hypertension (40%). *Insulin resistance and impaired glucose tolerance (40%)/diabetes mellitus (20%). *Obstructive sleep apnea – due to soft tissue swelling […] Ischaemic heart disease and cerebrovascular disease.”

“Management of acromegaly[:] The management strategy depends on the individual patient and also on the tumour size. Lowering of GH is essential in all situations […] Transsphenoidal surgery […] is usually the first line for treatment in most centres. *Reported cure rates vary: 40-91% for microadenomas and 10-48% for macroadenomas, depending on surgical expertise. […] Using the definition of post-operative cure as mean GH <2.5 micrograms/L, the reported recurrence rate is low (6% at 5 years). Radiotherapy […] is usually reserved for patients following unsuccessful transsphenoidal surgery, only occasionally is it used as [primary] therapy. […] normalization of mean GH may take several years and, during this time, adjunctive medical treatment (usually with somatostatin analogues) is required. […] Radiotherapy can induce GH deficiency which may need GH therapy. […] Somatostatin analogues lead to suppresion of GH secretion in 20-60% of patients with acromegaly. […] some patients are partial responders, and although somatostatin analogues will lead to lowering of mean GH, they do not suppress to normal despite dose escalation. These drugs may be used as [primary] therapy where the tumour does not cause mass effects or in patients who have received surgery and/or radiotherapy who have elevated mean GH. […] Dopamine agonists […] lead to lowering of GH levels but, very rarely, lead to normalization of GH or IGF-1 (<30%). They may be helpful, particularly if there is coexistent secretion of PRL, and, in these cases, there may be significant tumour shrinkage. […] GH receptor antagonists [are] [i]ndicated for somatostatin non-responders.”

“Cushing’s syndrome is an illness resulting from excess cortisol secretion, which has a high mortality if left untreated. There are several causes of hypercortisolaemia which must be differentiated, and the commonest cause is iatrogenic (oral, inhaled, or topical steroids). […] ACTH-dependent Cushing’s must be differentiated from ACTH-independent disease (usually due to an adrenal adenoma, or, rarely, carcinoma […]). Once a diagnosis of ACTH-dependent disease has been established, it is important to differentiate between pituitary-dependent (Cushing’s disease) and ectopic secretion. […] [Cushing’s disease is rare;] annual incidence approximately 2/million. The vast majority of Cushing’s syndrome is due to a pituitary ACTH-secreting corticotroph microadenoma. […] The features of Cushing’s syndrome are progressive and may be present for several years prior to diagnosis. […] *Facial appearance – round plethoric complexion, acne and hirsutism, thinning of scalp hair. *Weight gain – truncal obesity, buffalo hump […] *Skin – thin and fragile […] easy bruising […] *Proximal muscle weakness. *Mood disturbance – labile, depression, insomnia, psychosis. *Menstrual disturbance. *Low libido and impotence. […] Associated features [include:] *Hypertension (>50%) due to mineralocorticoid effects of cortisol […] *Impaired glucose tolerance/diabetes mellitus (30%). *Osteopenia and osteoporosis […] *Vascular disease […] *Susceptibility to infections. […] Cushing’s is associated with a hypercoagulable state, with increased cardiovascular thrombotic risks. […] Hypercortisolism suppresses the thyroidal, gonadal, and GH axes, leading to lowered levels of TSH and thyroid hormones as well as reduced gonadotrophins, gonadal steroids, and GH.”

“Treatment of Cushing’s disease[:] Transsphenoidal surgery [is] the first-line option in most cases. […] Pituitary radiotherapy [is] usually administered as second-line treatment, following unsuccessful transsphenoidal surgery. […] Medical treatment [is] indicated during the preoperative preparation of patients or while awaiting radiotherapy to be effective or if surgery or radiotherapy are contraindicated. *Inhibitors of steroidogenesis: metyrapone is usually used first-line, but ketoconazole should be used as first-line in children […] Disadvantage of these agents inhibiting steroidogenesis is the need to increase the dose to maintain control, as ACTH secretion will increase as cortisol concentrations decrease. […] Successful treatment (surgery or radiotherapy) of Cushing’s disease leads to cortisol deficiency and, therefore, glucocorticoid replacement therapy is essential. […] *Untreated [Cushing’s] disease leads to an approximately 30-50% mortality at 5 years, owing to vascular disease and susceptibility to infections. *Treated Cushing’s syndrome has a good prognosis […] *Although the physical features and severe psychological disorders associated with Cushing’s improve or resolve within weeks or months of successful treatment, more subtle mood disturbance may persist for longer. Adults may also have impaired cognitive function. […] it is likely that there is an cardiovascular risk. *Osteoporosis will usually resolve in children but may not improve significantly in older patients. […] *Hypertension has been shown to resolve in 80% and diabetes mellitus in up to 70%. *Recent data suggests that mortality even with successful treatment of Cushing’s is increased significantly.”

“The term incidentaloma refers to an incidentally detected lesion that is unassociated with hormonal hyper- or hyposecretion and has a benign natural history. The increasingly frequent detection of these lesions with technological improvements and more widespread use of sophisticated imaging has led to a management challenge – which, if any, lesions need investigation and/or treatment, and what is the optimal follow-up strategy (if required at all)? […] *Imaging studies using MRI demonstrate pituitary microadenomas in approximately 10% of normal volunteers. […] Clinically significant pituitary tumours are present in about 1 in 1,000 patients. […] Incidentally detected microadenomas are very unlikely (<10%) to increase in size whereas larger incidentally detected meso- and macroadenomas are more likely (40-50%) to enlarge. Thus, conservative management in selected patients may be appropriate for microadenomas which are incidentally detected […]. Macroadenomas should be treated, if possible.”

“Non-functioning pituitary tumours […] are unassociated with clinical syndromes of anterior pituitary hormone excess. […] Non-functioning pituitary tumours (NFA) are the commonest pituitary macroadenoma. They represent around 28% of all pituitary tumours. […] 50% enlarge, if left untreated, at 5 years. […] Tumour behaviour is variable, with some tumours behaving in a very indolent, slow-growing manner and others invading the sphenoid and cavernous sinus. […] At diagnosis, approximately 50% of patients are gonadotrophin-deficient. […] The initial definitive management in virtually every case is surgical. This removes mass effects and may lead to some recovery of pituitary function in around 10%. […] The use of post-operative radiotherapy remains controversial. […] The regrowth rate at 10 years without radiotherapy approaches 45% […] administration of post-operative radiotherapy reduces this regrowth rate to <10%. […] however, there are sequelae to radiotherapy – with a significant long-term risk of hypopituitarism and a possible risk of visual deterioration and malignancy in the field of radiation. […] Unlike the case for GH- and PRL-secreting tumours, medical therapy for NFAs is usually unhelpful […] Gonadotrophinomas […] are tumours that arise from the gonadotroph cells of the pituitary gland and produce FSH, LH, or the α subunit. […] they are usually silent and unassociated with excess detectable secretion of LH and FSH […] [they] present in the same manner as other non-functioning pituitary tumours, with mass effects and hypopituitarism […] These tumours are managed as non-functioning tumours.”

“The posterior lobe of the pituitary gland arises from the forebrain and comprises up to 25% of the normal adult pituitary gland. It produces arginine vasopressin and oxytocin. […] Oxytoxin has no known role in ♂ […] In ♀, oxytoxin contracts the pregnant uterus and also causes breast duct smooth muscle contraction, leading to breast milk ejection during breastfeeding. […] However, oxytoxin deficiency has no known adverse effect on parturition or breastfeeding. […] Arginine vasopressin is the major determinant of renal water excretion and, therefore, fluid balance. It’s main action is to reduce free water clearance. […] Many substances modulate vasopressin secretion, including the catecholamines and opioids. *The main site of action of vasopressin is in the collecting duct and the thick ascending loop of Henle […] Diabetes Insipidus (DI) […] is defined as the passage of large volumes (>3L/24h) of dilute urine (osmolality <300mOsm/kg). [It may be] [d]ue to deficiency of circulating arginine vasopressin [or] [d]ue to renal resistance to vasopressin.” […lots of other causes as well – trauma, tumours, inflammation, infection, vascular, drugs, genetic conditions…]

Hyponatraemia […] Incidence *1-6% of hospital admissions Na<130mmol/L. *15-22% hospital admissions Na<135mmol/L. […] True clinically apparent hyponatraemia is associated with either excess water or salt deficiency. […] Features *Depend on the underlying cause and also on the rate of development of hyponatraemia. May develop once sodium reaches 115mmol/L or earlier if the fall is rapid. Level at 100mmol/L or less is life-threatening. *Features of excess water are mainly neurological because of brain injury […] They include confusion and headache, progressing to seizures and coma. […] SIADH [Syndrome of Inappropriate ADH, US] is a common cause of hyponatraemia. […] The elderly are more prone to SIADH, as they are unable to suppress ADH as efficiently […] ↑ risk of hyponatraemia with SSRIs. […] rapid overcorrection of hyponatraemia may cause central pontine myelinolysis (demyelination).”

“The hypothalamus releases hormones that act as releasing hormones at the anterior pituitary gland. […] The commonest syndrome to be associated with the hypothalamus is abnormal GnRH secretion, leading to reduced gonadotrophin secretion and hypogonadism. Common causes are stress, weight loss, and excessive exercise.”

January 14, 2018 Posted by | Books, Cancer/oncology, Cardiology, Diabetes, Epidemiology, Medicine, Nephrology, Neurology, Ophthalmology, Pharmacology | Leave a comment

A few diabetes papers of interest

i. Type 2 Diabetes in the Real World: The Elusive Nature of Glycemic Control.

“Despite U.S. Food and Drug Administration (FDA) approval of over 40 new treatment options for type 2 diabetes since 2005, the latest data from the National Health and Nutrition Examination Survey show that the proportion of patients achieving glycated hemoglobin (HbA1c) <7.0% (<53 mmol/mol) remains around 50%, with a negligible decline between the periods 2003–2006 and 2011–2014. The Healthcare Effectiveness Data and Information Set reports even more alarming rates, with only about 40% and 30% of patients achieving HbA1c <7.0% (<53 mmol/mol) in the commercially insured (HMO) and Medicaid populations, respectively, again with virtually no change over the past decade. A recent retrospective cohort study using a large U.S. claims database explored why clinical outcomes are not keeping pace with the availability of new treatment options. The study found that HbA1c reductions fell far short of those reported in randomized clinical trials (RCTs), with poor medication adherence emerging as the key driver behind the disconnect. In this Perspective, we examine the implications of these findings in conjunction with other data to highlight the discrepancy between RCT findings and the real world, all pointing toward the underrealized promise of FDA-approved therapies and the critical importance of medication adherence. While poor medication adherence is not a new issue, it has yet to be effectively addressed in clinical practice — often, we suspect, because it goes unrecognized. To support the busy health care professional, innovative approaches are sorely needed.”

“To better understand the differences between usual care and clinical trial HbA1c results, multivariate regression analysis assessed the relative contributions of key biobehavioral factors, including baseline patient characteristics, drug therapy, and medication adherence (21). Significantly, the key driver was poor medication adherence, accounting for 75% of the gap […]. Adherence was defined […] as the filling of one’s diabetes prescription often enough to cover ≥80% of the time one was recommended to be taking the medication (34). By this metric, proportion of days covered (PDC) ≥80%, only 29% of patients were adherent to GLP-1 RA treatment and 37% to DPP-4 inhibitor treatment. […] These data are consistent with previous real-world studies, which have demonstrated that poor medication adherence to both oral and injectable antidiabetes agents is very common (3537). For example, a retrospective analysis [of] adults initiating oral agents in the DPP-4 inhibitor (n = 61,399), sulfonylurea (n = 134,961), and thiazolidinedione (n = 42,012) classes found that adherence rates, as measured by PDC ≥80% at the 1-year mark after the initial prescription, were below 50% for all three classes, at 47.3%, 41.2%, and 36.7%, respectively (36). Rates dropped even lower at the 2-year follow-up (36)”

“Our current ability to assess adherence and persistence is based primarily on review of pharmacy records, which may underestimate the extent of the problem. For example, using the definition of adherence of the Centers for Medicare & Medicaid Services — PDC ≥80% — a patient could miss up to 20% of days covered and still be considered adherent. In retrospective studies of persistence, the permissible gap after the last expected refill date often extends up to 90 days (39,40). Thus, a patient may have a gap of up to 90 days and still be considered persistent.

Additionally, one must also consider the issue of primary nonadherence; adherence and persistence studies typically only include patients who have completed a first refill. A recent study of e-prescription data among 75,589 insured patients found that nearly one-third of new e-prescriptions for diabetes medications were never filled (41). Finally, none of these measures take into account if the patient is actually ingesting or injecting the medication after acquiring his or her refills.”

“Acknowledging and addressing the problem of poor medication adherence is pivotal because of the well-documented dire consequences: a greater likelihood of long-term complications, more frequent hospitalizations, higher health care costs, and elevated mortality rates (4245). In patients younger than 65, hospitalization risk in one study (n = 137,277) was found to be 30% at the lowest level of adherence to antidiabetes medications (1–19%) versus 13% at the highest adherence quintile (80–100%) […]. In patients over 65, a separate study (n = 123,235) found that all-cause hospitalization risk was 37.4% in adherent cohorts (PDC ≥80%) versus 56.2% in poorly adherent cohorts (PDC <20%) (45). […] Furthermore, for every 1,000 patients who increased adherence to their antidiabetes medications by just 1%, the total medical cost savings was estimated to be $65,464 over 3 years (45). […] “for reasons that are still unclear, the N.A. [North American] patient groups tend to have lower compliance and adherence compared to global rates during large cardiovascular studies” (46,47).”

“There are many potential contributors to poor medication adherence, including depressive affect, negative treatment perceptions, lack of patient-physician trust, complexity of the medication regimen, tolerability, and cost (48). […] A recent review of interventions addressing problematic medication adherence in type 2 diabetes found that few strategies have been shown consistently to have a marked positive impact, particularly with respect to HbA1c lowering, and no single intervention was identified that could be applied successfully to all patients with type 2 diabetes (53). Additional evidence indicates that improvements resulting from the few effective interventions, such as pharmacy-based counseling or nurse-managed home telemonitoring, often wane once the programs end (54,55). We suspect that the efficacy of behavioral interventions to address medication adherence will continue to be limited until there are more focused efforts to address three common and often unappreciated patient obstacles. First, taking diabetes medications is a burdensome and often difficult activity for many of our patients. Rather than just encouraging patients to do a better job of tolerating this burden, more work is needed to make the process easier and more convenient. […] Second, poor medication adherence often represents underlying attitudinal problems that may not be a strictly behavioral issue. Specifically, negative beliefs about prescribed medications are pervasive among patients, and behavioral interventions cannot be effective unless these beliefs are addressed directly (35). […] Third, the issue of access to medications remains a primary concern. A study by Kurlander et al. (51) found that patients selectively forgo medications because of cost; however, noncost factors, such as beliefs, satisfaction with medication-related information, and depression, are also influential.”

ii. Diabetes Research and Care Through the Ages. An overview article which might be of interest especially to people who’re not much familiar with the history of diabetes research and -treatment (a topic which is also very nicely covered in Tattersall’s book). Despite including a historical review of various topics, it also includes many observations about e.g. current (and future?) practice. Some random quotes:

“Arnoldo Cantani established a new strict level of treatment (9). He isolated his patients “under lock and key, and allowed them absolutely no food but lean meat and various fats. In the less severe cases, eggs, liver, and shell-fish were permitted. For drink the patients received water, plain or carbonated, and dilute alcohol for those accustomed to liquors, the total fluid intake being limited to one and one-half to two and one-half liters per day” (6).

Bernhard Naunyn encouraged a strict carbohydrate-free diet (6,10). He locked patients in their rooms for 5 months when necessary for “sugar-freedom” (6).” […let’s just say that treatment options have changed slightly over time – US]

“The characteristics of insulin preparations include the purity of the preparation, the concentration of insulin, the species of origin, and the time course of action (onset, peak, duration) (25). From the 1930s to the early 1950s, one of the major efforts made was to develop an insulin with extended action […]. Most preparations contained 40 (U-40) or 80 (U-80) units of insulin per mL, with U-10 and U-20 eliminated in the early 1940s. U-100 was introduced in 1973 and was meant to be a standard concentration, although U-500 had been available since the early 1950s for special circumstances. Preparations were either of mixed beef and pork origin, pure beef, or pure pork. There were progressive improvements in the purity of preparations as chemical techniques improved. Prior to 1972, conventional preparations contained 8% noninsulin proteins. […] In the early 1980s, “human” insulins were introduced (26). These were made either by recombinant DNA technology in bacteria (Escherichia coli) or yeast (Saccharomyces cerevisiae) or by enzymatic conversion of pork insulin to human insulin, since pork differed by only one amino acid from human insulin. The powerful nature of recombinant DNA technology also led to the development of insulin analogs designed for specific effects. These include rapid-acting insulin analogs and basal insulin analogs.”

“Until 1996, the only oral medications available were biguanides and sulfonylureas. Since that time, there has been an explosion of new classes of oral and parenteral preparations. […] The management of type 2 diabetes (T2D) has undergone rapid change with the introduction of several new classes of glucose-lowering therapies. […] the treatment guidelines are generally clear in the context of using metformin as the first oral medication for T2D and present a menu approach with respect to the second and third glucose-lowering medication (3032). In order to facilitate this decision, the guidelines list the characteristics of each medication including side effects and cost, and the health care provider is expected to make a choice that would be most suited for patient comorbidities and health care circumstances. This can be confusing and contributes to the clinical inertia characteristic of the usual management of T2D (33).”

“Perhaps the most frustrating barrier to optimizing diabetes management is the frequent occurrence of clinical inertia (whenever the health care provider does not initiate or intensify therapy appropriately and in a timely fashion when therapeutic goals are not reached). More broadly, the failure to advance therapy in an appropriate manner can be traced to physician behaviors, patient factors, or elements of the health care system. […] Despite clear evidence from multiple studies, health care providers fail to fully appreciate that T2D is a progressive disease. T2D is associated with ongoing β-cell failure and, as a consequence, we can safely predict that for the majority of patients, glycemic control will deteriorate with time despite metformin therapy (35). Continued observation and reinforcement of the current therapeutic regimen is not likely to be effective. As an example of real-life clinical inertia for patients with T2D on monotherapy metformin and an HbA1c of 7 to <8%, it took on the average 19 months before additional glucose-lowering therapy was introduced (36). The fear of hypoglycemia and weight gain are appropriate concerns for both patient and physician, but with newer therapies these undesirable effects are significantly diminished. In addition, health care providers must appreciate that achieving early and sustained glycemic control has been demonstrated to have long-term benefits […]. Clinicians have been schooled in the notion of a stepwise approach to therapy and are reluctant to initiate combination therapy early in the course of T2D, even if the combination intervention is formulated as a fixed-dose combination. […] monotherapy metformin failure rates with a starting HbA1c >7% are ∼20% per year (35). […] To summarize the current status of T2D at this time, it should be clearly emphasized that, first and foremost, T2D is characterized by a progressive deterioration of glycemic control. A stepwise medication introduction approach results in clinical inertia and frequently fails to meet long-term treatment goals. Early/initial combination therapies that are not associated with hypoglycemia and/or weight gain have been shown to be safe and effective. The added value of reducing CV outcomes with some of these newer medications should elevate them to a more prominent place in the treatment paradigm.”

iii. Use of Adjuvant Pharmacotherapy in Type 1 Diabetes: International Comparison of 49,996 Individuals in the Prospective Diabetes Follow-up and T1D Exchange Registries.

“The majority of those with type 1 diabetes (T1D) have suboptimal glycemic control (14); therefore, use of adjunctive pharmacotherapy to improve control has been of clinical interest. While noninsulin medications approved for type 2 diabetes have been reported in T1D research and clinical practice (5), little is known about their frequency of use. The T1D Exchange (T1DX) registry in the U.S. and the Prospective Diabetes Follow-up (DPV) registry in Germany and Austria are two large consortia of diabetes centers; thus, they provide a rich data set to address this question.

For the analysis, 49,996 pediatric and adult patients with diabetes duration ≥1 year and a registry update from 1 April 2015 to 1 July 2016 were included (19,298 individuals from 73 T1DX sites and 30,698 individuals from 354 DPV sites). Adjuvant medication use (metformin, glucagon-like peptide 1 [GLP-1] receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors, sodium–glucose cotransporter 2 [SGLT2] inhibitors, and other noninsulin diabetes medications including pramlintide) was extracted from participant medical records. […] Adjunctive agents, whose proposed benefits may include the ability to improve glycemic control, reduce insulin doses, promote weight loss, and suppress dysregulated postprandial glucagon secretion, have had little penetrance as part of the daily medical regimen of those in the registries studied. […] The use of any adjuvant medication was 5.4% in T1DX and 1.6% in DPV (P < 0.001). Metformin was the most commonly reported medication in both registries, with 3.5% in the T1DX and 1.3% in the DPV (P < 0.001). […] Use of adjuvant medication was associated with older age, higher BMI, and longer diabetes duration in both registries […] it is important to note that registry data did not capture the intent of adjuvant medications, which may have been to treat polycystic ovarian syndrome in women […here’s a relevant link, US].”

iv. Prevalence of and Risk Factors for Diabetic Peripheral Neuropathy in Youth With Type 1 and Type 2 Diabetes: SEARCH for Diabetes in Youth Study. I recently covered a closely related paper here (paper # 2) but the two papers cover different data sets so I decided it would be worth including this one in this post anyway. Some quotes:

“We previously reported results from a small pilot study comparing the prevalence of DPN in a subset of youth enrolled in the SEARCH for Diabetes in Youth (SEARCH) study and found that 8.5% of 329 youth with T1D (mean ± SD age 15.7 ± 4.3 years and diabetes duration 6.2 ± 0.9 years) and 25.7% of 70 youth with T2D (age 21.6 ± 4.1 years and diabetes duration 7.6 ± 1.8 years) had evidence of DPN (9). […this is the paper I previously covered here, US] Recently, we also reported the prevalence of microvascular and macrovascular complications in youth with T1D and T2D in the entire SEARCH cohort (10).

In the current study, we examined the cross-sectional and longitudinal risk factors for DPN. The aims were 1) to estimate prevalence of DPN in youth with T1D and T2D, overall and by age and diabetes duration, and 2) to identify risk factors (cross-sectional and longitudinal) associated with the presence of DPN in a multiethnic cohort of youth with diabetes enrolled in the SEARCH study.”

“The SEARCH Cohort Study enrolled 2,777 individuals. For this analysis, we excluded participants aged <10 years (n = 134), those with no antibody measures for etiological definition of diabetes (n = 440), and those with incomplete neuropathy assessment […] (n = 213), which reduced the analysis sample size to 1,992 […] There were 1,734 youth with T1D and 258 youth with T2D who participated in the SEARCH study and had complete data for the variables of interest. […] Seven percent of the participants with T1D and 22% of those with T2D had evidence of DPN.”

“Among youth with T1D, those with DPN were older (21 vs. 18 years, P < 0.0001), had a longer duration of diabetes (8.7 vs. 7.8 years, P < 0.0001), and had higher DBP (71 vs. 69 mmHg, P = 0.02), BMI (26 vs. 24 kg/m2, P < 0.001), and LDL-c levels (101 vs. 96 mg/dL, P = 0.01); higher triglycerides (85 vs. 74 mg/dL, P = 0.005); and lower HDL-c levels (51 vs. 55 mg/dL, P = 0.01) compared to those without DPN. The prevalence of DPN was 5% among nonsmokers vs. 10% among the current and former smokers (P = 0.001). […] Among youth with T2D, those with DPN were older (23 vs. 22 years, P = 0.01), had longer duration of diabetes (8.6 vs. 7.6 years; P = 0.002), and had lower HDL-c (40 vs. 43 mg/dL, P = 0.04) compared with those without DPN. The prevalence of DPN was higher among males than among females: 30% of males had DPN compared with 18% of females (P = 0.02). The prevalence of DPN was twofold higher in current smokers (33%) compared with nonsmokers (15%) and former smokers (17%) (P = 0.01). […] [T]he prevalence of DPN was further assessed by 5-year increment of diabetes duration in individuals with T1D or T2D […]. There was an approximately twofold increase in the prevalence of DPN with an increase in duration of diabetes from 5–10 years to >10 years for both the T1D group (5–13%) (P < 0.0001) and the T2D group (19–36%) (P = 0.02). […] in an unadjusted logistic regression model, youth with T2D were four times more likely to develop DPN compared with those with T1D, and though this association was attenuated, it remained significant independent of age, sex, height, and glycemic control (OR 2.99 [1.91; 4.67], P < 0.001)”.

“The prevalence estimates for DPN found in our study for youth with T2D are similar to those in the Australian cohort (8) but lower for youth with T1D than those reported in the Danish (7) and Australian (8) cohorts. The nationwide Danish Study Group for Diabetes in Childhood reported a prevalence of 62% among 339 adolescents and youth with T1D (age 12–27 years, duration 9–25 years, and HbA1c 9.7 ± 1.7%) using the vibration perception threshold to assess DPN (7). The higher prevalence in this cohort compared with ours (62 vs. 7%) could be due to the longer duration of diabetes (9–25 vs. 5–13 years) and reliance on a single measure of neuropathy (vibration perception threshold) as opposed to our use of the MNSI, which includes vibration as well as other indicators of neuropathy. In the Australian study, Eppens et al. (8) reported abnormalities in peripheral nerve function in 27% of the 1,433 adolescents with T1D (median age 15.7 years, median diabetes duration 6.8 years, and mean HbA1c 8.5%) and 21% of the 68 adolescents with T2D (median age 15.3 years, median diabetes duration 1.3 years, and mean HbA1c 7.3%) based on thermal and vibration perception threshold. These data are thus reminiscent of the persistent inconsistencies in the definition of DPN, which are reflected in the wide range of prevalence estimates being reported.”

“The alarming rise in rates of DPN for every 5-year increase in duration, coupled with poor glycemic control and dyslipidemia, in this cohort reinforces the need for clinicians rendering care to youth with diabetes to be vigilant in screening for DPN and identifying any risk factors that could potentially be modified to alter the course of the disease (2830). The modifiable risk factors that could be targeted in this young population include better glycemic control, treatment of dyslipidemia, and smoking cessation (29,30) […]. The sharp increase in rates of DPN over time is a reminder that DPN is one of the complications of diabetes that must be a part of the routine annual screening for youth with diabetes.”

v. Diabetes and Hypertension: A Position Statement by the American Diabetes Association.

“Hypertension is common among patients with diabetes, with the prevalence depending on type and duration of diabetes, age, sex, race/ethnicity, BMI, history of glycemic control, and the presence of kidney disease, among other factors (13). Furthermore, hypertension is a strong risk factor for atherosclerotic cardiovascular disease (ASCVD), heart failure, and microvascular complications. ASCVD — defined as acute coronary syndrome, myocardial infarction (MI), angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin — is the leading cause of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. Numerous studies have shown that antihypertensive therapy reduces ASCVD events, heart failure, and microvascular complications in people with diabetes (48). Large benefits are seen when multiple risk factors are addressed simultaneously (9). There is evidence that ASCVD morbidity and mortality have decreased for people with diabetes since 1990 (10,11) likely due in large part to improvements in blood pressure control (1214). This Position Statement is intended to update the assessment and treatment of hypertension among people with diabetes, including advances in care since the American Diabetes Association (ADA) last published a Position Statement on this topic in 2003 (3).”

“Hypertension is defined as a sustained blood pressure ≥140/90 mmHg. This definition is based on unambiguous data that levels above this threshold are strongly associated with ASCVD, death, disability, and microvascular complications (1,2,2427) and that antihypertensive treatment in populations with baseline blood pressure above this range reduces the risk of ASCVD events (46,28,29). The “sustained” aspect of the hypertension definition is important, as blood pressure has considerable normal variation. The criteria for diagnosing hypertension should be differentiated from blood pressure treatment targets.

Hypertension diagnosis and management can be complicated by two common conditions: masked hypertension and white-coat hypertension. Masked hypertension is defined as a normal blood pressure in the clinic or office (<140/90 mmHg) but an elevated home blood pressure of ≥135/85 mmHg (30); the lower home blood pressure threshold is based on outcome studies (31) demonstrating that lower home blood pressures correspond to higher office-based measurements. White-coat hypertension is elevated office blood pressure (≥140/90 mmHg) and normal (untreated) home blood pressure (<135/85 mmHg) (32). Identifying these conditions with home blood pressure monitoring can help prevent overtreatment of people with white-coat hypertension who are not at elevated risk of ASCVD and, in the case of masked hypertension, allow proper use of medications to reduce side effects during periods of normal pressure (33,34).”

“Diabetic autonomic neuropathy or volume depletion can cause orthostatic hypotension (35), which may be further exacerbated by antihypertensive medications. The definition of orthostatic hypotension is a decrease in systolic blood pressure of 20 mmHg or a decrease in diastolic blood pressure of 10 mmHg within 3 min of standing when compared with blood pressure from the sitting or supine position (36). Orthostatic hypotension is common in people with type 2 diabetes and hypertension and is associated with an increased risk of mortality and heart failure (37).

It is important to assess for symptoms of orthostatic hypotension to individualize blood pressure goals, select the most appropriate antihypertensive agents, and minimize adverse effects of antihypertensive therapy.”

“Taken together, […] meta-analyses consistently show that treating patients with baseline blood pressure ≥140 mmHg to targets <140 mmHg is beneficial, while more intensive targets may offer additional though probably less robust benefits. […] Overall, compared with people without diabetes, the relative benefits of antihypertensive treatment are similar, and absolute benefits may be greater (5,8,40). […] Multiple-drug therapy is often required to achieve blood pressure targets, particularly in the setting of diabetic kidney disease. However, the use of both ACE inhibitors and ARBs in combination is not recommended given the lack of added ASCVD benefit and increased rate of adverse events — namely, hyperkalemia, syncope, and acute kidney injury (7173). Titration of and/or addition of further blood pressure medications should be made in a timely fashion to overcome clinical inertia in achieving blood pressure targets. […] there is an absence of high-quality data available to guide blood pressure targets in type 1 diabetes. […] Of note, diastolic blood pressure, as opposed to systolic blood pressure, is a key variable predicting cardiovascular outcomes in people under age 50 years without diabetes and may be prioritized in younger adults (46,47). Though convincing data are lacking, younger adults with type 1 diabetes might more easily achieve intensive blood pressure levels and may derive substantial long-term benefit from tight blood pressure control.”

“Lifestyle management is an important component of hypertension treatment because it lowers blood pressure, enhances the effectiveness of some antihypertensive medications, promotes other aspects of metabolic and vascular health, and generally leads to few adverse effects. […] Lifestyle therapy consists of reducing excess body weight through caloric restriction, restricting sodium intake (<2,300 mg/day), increasing consumption of fruits and vegetables […] and low-fat dairy products […], avoiding excessive alcohol consumption […] (53), smoking cessation, reducing sedentary time (54), and increasing physical activity levels (55). These lifestyle strategies may also positively affect glycemic and lipid control and should be encouraged in those with even mildly elevated blood pressure.”

“Initial treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes: ACE inhibitors (65,66), angiotensin receptor blockers (ARBs) (65,66), thiazide-like diuretics (67), or dihydropyridine CCBs (68). For patients with albuminuria (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g creatinine), initial treatment should include an ACE inhibitor or ARB in order to reduce the risk of progressive kidney disease […]. In the absence of albuminuria, risk of progressive kidney disease is low, and ACE inhibitors and ARBs have not been found to afford superior cardioprotection when compared with other antihypertensive agents (69). β-Blockers may be used for the treatment of coronary disease or heart failure but have not been shown to reduce mortality as blood pressure–lowering agents in the absence of these conditions (5,70).”

vi. High Illicit Drug Abuse and Suicide in Organ Donors With Type 1 Diabetes.

“Organ donors with type 1 diabetes represent a unique population for research. Through a combination of immunological, metabolic, and physiological analyses, researchers utilizing such tissues seek to understand the etiopathogenic events that result in this disorder. The Network for Pancreatic Organ Donors with Diabetes (nPOD) program collects, processes, and distributes pancreata and disease-relevant tissues to investigators throughout the world for this purpose (1). Information is also available, through medical records of organ donors, related to causes of death and psychological factors, including drug use and suicide, that impact life with type 1 diabetes.

We reviewed the terminal hospitalization records for the first 100 organ donors with type 1 diabetes in the nPOD database, noting cause, circumstance, and mechanism of death; laboratory results; and history of illicit drug use. Donors were 45% female and 79% Caucasian. Mean age at time of death was 28 years (range 4–61) with mean disease duration of 16 years (range 0.25–52).”

“Documented suicide was found in 8% of the donors, with an average age at death of 21 years and average diabetes duration of 9 years. […] Similarly, a type 1 diabetes registry from the U.K. found that 6% of subjects’ deaths were attributed to suicide (2). […] Additionally, we observed a high rate of illicit substance abuse: 32% of donors reported or tested positive for illegal substances (excluding marijuana), and multidrug use was common. Cocaine was the most frequently abused substance. Alcohol use was reported in 35% of subjects, with marijuana use in 27%. By comparison, 16% of deaths in the U.K. study were deemed related to drug misuse (2).”

“We fully recognize the implicit biases of an organ donor–based population, which may not be […’may not be’ – well, I guess that’s one way to put it! – US] directly comparable to the general population. Nevertheless, the high rate of suicide and drug use should continue to spur our energy and resources toward caring for the emotional and psychological needs of those living with type 1 diabetes. The burden of type 1 diabetes extends far beyond checking blood glucose and administering insulin.”

January 10, 2018 Posted by | Cardiology, Diabetes, Epidemiology, Medicine, Nephrology, Neurology, Pharmacology, Psychiatry, Studies | Leave a comment

Depression (II)

I have added some more quotes from the last half of the book as well as some more links to relevant topics below.

“The early drugs used in psychiatry were sedatives, as calming a patient was probably the only treatment that was feasible and available. Also, it made it easier to manage large numbers of individuals with small numbers of staff at the asylum. Morphine, hyoscine, chloral, and later bromide were all used in this way. […] Insulin coma therapy came into vogue in the 1930s following the work of Manfred Sakel […] Sakel initially proposed this treatment as a cure for schizophrenia, but its use gradually spread to mood disorders to the extent that asylums in Britain opened so-called insulin units. […] Recovery from the coma required administration of glucose, but complications were common and death rates ranged from 1–10 per cent. Insulin coma therapy was initially viewed as having tremendous benefits, but later re-examinations have highlighted that the results could also be explained by a placebo effect associated with the dramatic nature of the process or, tragically, because deprivation of glucose supplies to the brain may have reduced the person’s reactivity because it had induced permanent damage.”

“[S]ome respected scientists and many scientific journals remain ambivalent about the empirical evidence for the benefits of psychological therapies. Part of the reticence appears to result from the lack of very large-scale clinical trials of therapies (compared to international, multi-centre studies of medication). However, a problem for therapy research is that there is no large-scale funding from big business for therapy trials […] It is hard to implement optimum levels of quality control in research studies of therapies. A tablet can have the same ingredients and be prescribed in almost exactly the same way in different treatment centres and different countries. If a patient does not respond to this treatment, the first thing we can do is check if they receive the right medication in the correct dose for a sufficient period of time. This is much more difficult to achieve with psychotherapy and fuels concerns about how therapy is delivered and potential biases related to researcher allegiance (i.e. clinical centres that invent a therapy show better outcomes than those that did not) and generalizability (our ability to replicate the therapy model exactly in a different place with different therapists). […] Overall, the ease of prescribing a tablet, the more traditional evidence-base for the benefits of medication, and the lack of availability of trained therapists in some regions means that therapy still plays second fiddle to medications in the majority of treatment guidelines for depression. […] The mainstay of treatments offered to individuals with depression has changed little in the last thirty to forty years. Antidepressants are the first-line intervention recommended in most clinical guidelines”.

“[W]hilst some cases of mild–moderate depression can benefit from antidepressants (e.g. chronic mild depression of several years’ duration can often respond to medication), it is repeatedly shown that the only group who consistently benefit from antidepressants are those with severe depression. The problem is that in the real world, most antidepressants are actually prescribed for less severe cases, that is, the group least likely to benefit; which is part of the reason why the argument about whether antidepressants work is not going to go away any time soon.”

“The economic argument for therapy can only be sustained if it is shown that the long-term outcome of depression (fewer relapses and better quality of life) is improved by receiving therapy instead of medication or by receiving both therapy and medication. Despite claims about how therapies such as CBT, behavioural activation, IPT, or family therapy may work, the reality is that many of the elements included in these therapies are the same as elements described in all the other effective therapies (sometimes referred to as empirically supported therapies). The shared elements include forming a positive working alliance with the depressed person, sharing the model and the plan for therapy with the patient from day one, and helping the patient engage in active problem-solving, etc. Given the degree of overlap, it is hard to make a real case for using one empirically supported therapy instead of another. Also, there are few predictors (besides symptom severity and personal preference) that consistently show who will respond to one of these therapies rather than to medication. […] One of the reasons for some scepticism about the value of therapies for treating depression is that it has proved difficult to demonstrate exactly what mediates the benefits of these interventions. […] despite the enthusiasm for mindfulness, there were fewer than twenty high-quality research trials on its use in adults with depression by the end of 2015 and most of these studies had fewer than 100 participants. […] exercise improves the symptoms of depression compared to no treatment at all, but the currently available studies on this topic are less than ideal (with many problems in the design of the study or sample of participants included in the clinical trial). […] Exercise is likely to be a better option for those individuals whose mood improves from participating in the experience, rather than someone who is so depressed that they feel further undermined by the process or feel guilty about ‘not trying hard enough’ when they attend the programme.”

“Research […] indicates that treatment is important and a study from the USA in 2005 showed that those who took the prescribed antidepressant medications had a 20 per cent lower rate of absenteeism than those who did not receive treatment for their depression. Absence from work is only one half of the depression–employment equation. In recent times, a new concept ‘presenteeism’ has been introduced to try to describe the problem of individuals who are attending their place of work but have reduced efficiency (usually because their functioning is impaired by illness). As might be imagined, presenteeism is a common issue in depression and a study in the USA in 2007 estimated that a depressed person will lose 5–8 hours of productive work every week because the symptoms they experience directly or indirectly impair their ability to complete work-related tasks. For example, depression was associated with reduced productivity (due to lack of concentration, slowed physical and mental functioning, loss of confidence), and impaired social functioning”.

“Health economists do not usually restrict their estimates of the cost of a disorder simply to the funds needed for treatment (i.e. the direct health and social care costs). A comprehensive economic assessment also takes into account the indirect costs. In depression these will include costs associated with employment issues (e.g. absenteeism and presenteeism; sickness benefits), costs incurred by the patient’s family or significant others (e.g. associated with time away from work to care for someone), and costs arising from premature death such as depression-related suicides (so-called mortality costs). […] Studies from around the world consistently demonstrate that the direct health care costs of depression are dwarfed by the indirect costs. […] Interestingly, absenteeism is usually estimated to be about one-quarter of the costs of presenteeism.”

Jakob Klaesi. António Egas Moniz. Walter Jackson Freeman II.
Electroconvulsive therapy.
Vagal nerve stimulation.
Chlorpromazine. Imipramine. Tricyclic antidepressant. MAOIs. SSRIs. John CadeMogens Schou. Lithium carbonate.
Psychoanalysis. CBT.
Thomas Szasz.
Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration (Kirsch et al.).
Chronobiology. Chronobiotics. Melatonin.
Eric Kandel. BDNF.
The global burden of disease (Murray & Lopez) (the author discusses some of the data included in that publication).

January 8, 2018 Posted by | Books, Health Economics, Medicine, Pharmacology, Psychiatry, Psychology | Leave a comment

Endocrinology (part I – thyroid)

Handbooks like these are difficult to blog, but I decided to try anyway. The first 100 pages or so of the book deals with the thyroid gland. Some observations of interest below.

“Biosynthesis of thyroid hormones requires iodine as substrate. […] The thyroid is the only source of T4. The thyroid secretes 20% of circulating T3; the remainder is generated in extraglandular tissues by the conversion of T4 to T3 […] In the blood, T4 and T3 are almost entirely bound to plasma proteins. […] Only the free or unbound hormone is available to tissues. The metabolic state correlates more closely with the free than the total hormone concentration in the plasma. The relatively weak binding of T3 accounts for its more rapid onset and offset of action. […] The levels of thyroid hormone in the blood are tightly controlled by feedback mechanisms involved in the hypothalamo-pituitary-thyroid (HPT) axis“.

“Annual check of thyroid function [is recommended] in the annual review of diabetic patients.”

“The term thyrotoxicosis denotes the clinical, physiological, and biochemical findings that result when the tissues are exposed to excess thyroid hormone. It can arise in a variety of ways […] It is essential to establish a specific diagnosis […] The term hyperthyroidism should be used to denote only those conditions in which hyperfunction of the thyroid leads to thyrotoxicosis. […] [Thyrotoxicosis is] 10 x more common in ♀ than in ♂ in the UK. Prevalence is approximately 2% of the ♀ population. […] Subclinical hyperthyroidism is defined as low serum thyrotropin (TSH) concentration in patients with normal levels of T4 and T3. Subtle symptoms and signs of thyrotoxicosis may be present. […] There is epidemiological evidence that subclinical hyperthyroidism is a risk factor for the development of atrial fibrillation or osteoporosis.1 Meta-analyses suggest a 41% increase in all-cause mortality.2 […] Thyroid crisis [storm] represents a rare, but life-threatening, exacerbation of the manifestations of thyrotoxicosis. […] the condition is associated with a significant mortality (30-50%, depending on series) […]. Thyroid crisis develops in hyperthyroid patients who: *Have an acute infection. *Undergo thyroidal or non-thyroidal surgery or (rarely) radioiodine treatment.”

“[Symptoms and signs of hyperthyroidism (all forms):] *Hyperactivity, irritability, altered mood, insomnia. *Heat intolerance, sweating. […] *Fatigue, weakness. *Dyspnoea. *Weight loss with appetite (weight gain in 10% of patients). *Pruritus. […] *Thirst and polyuria. *Oligomenorrhoea or amenorrhoea, loss of libido, erectile dysfunction (50% of men may have sexual dysfunction). *Warm, moist skin. […] *Hair loss. *Muscle weakness and wasting. […] Manifestations of Graves’s disease (in addition to [those factors already mentioned include:]) *Diffuse goitre. *Ophthalmopathy […] A feeling of grittiness and discomfort in the eye. *Retrobulbar pressure or pain, eyelid lag or retraction. […] *Exophthalmos (proptosis) […] Optic neuropathy.”

“Two alternative regimens are practiced for Graves’s disease: dose titration and block and replace. […] The [primary] aim [of the dose titration regime] is to achieve a euthyroid state with relatively high drug doses and then to maintain euthyroidism with a low stable dose. […] This regimen has a lower rate of side effects than the block and replace regimen. The treatment is continued for 18 months, as this appears to represent the length of therapy which is generally optimal in producing the remission rate of up to 40% at 5 years after discontinuing therapy. *Relapses are most likely to occur within the first year […] Men have a higher recurrence rate than women. *Patients with multinodular goitres and thyrotoxicosis always relapse on cessation of antithyroid medication, and definite treatment with radioiodine or surgery is usually advised. […] Block and replace regimen *After achieving a euthyroid state on carbimazole alone, carbimazole at a dose of 40mg daily, together with T4 at a dose of 100 micrograms, can be prescribed. This is usually continued for 6 months. *The main advantages are fewer hospital visits for checks of thyroid function and shorter duration of treatment.”

“Radioiodine treatment[:] Indications: *Definite treatment of multinodular goitre or adenoma. *Relapsed Graves’s disease. […] *Radioactive iodine-131 is administered orally as a capsule or a drink. *There is no universal agreement regarding the optimal dose. […] The recommendation is to administer enough radioiodine to achieve euthyroidism, with the acceptance of a moderate rate of hypothyroidism, e.g. 15-20% at 2 years. […] In general, 50-70% of patients have restored normal thyroid function within 6-8 weeks of receiving radioiodine. […] The prevalence of hypothyroidism is about 50% at 10 years and continues to increase thereafter.”

“Thyrotoxicosis occurs in about 0.2% of pregnancies. […] *Diagnosis of thyrotoxicosis during pregnancy may be difficult or delayed. *Physiological changes of pregnancy are similar to those of hyperthyroidism. […] 5-7% of ♀ develop biochemical evidence of thyroid dysfunction after delivery. An incidence is seen in patients with type I diabetes mellitus (25%) […] One-third of affected ♀ with post-partum thyroiditis develop symptoms of hypothyroidism […] There is a suggestion of an risk of post-partum depression in those with hypothyroidism. […] *The use of iodides and radioiodine is contraindicated in pregnancy. *Surgery is rarely performed in pregnancy. It is reserved for patients not responding to ATDs [antithyroid drugs, US]. […] Hyperthyroid ♀ who want to conceive should attain euthyroidism before conception since uncontrolled hyperthyroidism is associated with an an risk of congenital abnormalities (stillbirth and cranial synostosis are the most serious complications).”

“Nodular thyroid disease denotes the presence of single or multiple palpable or non-palpable nodules within the thyroid gland. […] *Clinically apparent thyroid nodules are evident in ~5% of the UK population. […] Thyroid nodules always raise the concern of cancer, but <5% are cancerous. […] clinically detectable thyroid cancer is rare. It accounts for <1% of all cancer and <0.5% of cancer deaths. […] Thyroid cancers are commonest in adults aged 40-50 and rare in children [incidence of 0.2-5 per million per year] and adolescents. […] History should concentrate on: *An enlarging thyroid mass. *A previous history of radiation […] family history of thyroid cancer. *The development of hoarseness or dysphagia. *Nodules are more likely to be malignant in patients <20 or >60 years. *Thyroid nodules are more common in ♀ but more likely to be malignant in ♂. […] Physical findings suggestive of malignancy include a firm or hard, non-tender nodule, a recent history of enlargement, fixation to adjacent tissue, and the presence of regional lymphadenopathy. […] Thyroid nodules may be described as adenomas if the follicular cell differentiation is enclosed within a capsule; adenomatous when the lesions are circumscribed but not encapsulated. *The most common benign thyroid tumours are the nodules of multinodular goitres (colloid nodules) and follicular adenomas. […] Autonomously functioning thyroid adenomas (or nodules) are benign tumours that produce thyroid hormone. Clinically, they present as a single nodule that is hyperfunctioning […], sometimes causing hyperthyroidism.”

“Inflammation of the thyroid gland often leads to a transient thyrotoxicosis followed by hypothyroidism. Overt hypothyroidism caused by autoimmunity has two main forms: Hashimoto’s (goitrous) thyroiditis and atrophic thyroiditis. […] Hashimoto’s thyroiditis [is] [c]haracterized by a painless, variable-sized goitre with rubbery consistency and an irregular surface. […] Occasionally, patients present with thyrotoxicosis in association with a thyroid gland that is unusually firm […] Atrophic thyroiditis [p]robably indicates end-stage thyroid disease. These patients do not have goitre and are antibody [positive]. […] The long-term prognosis of patients with chronic thyroiditis is good because hypothyroidism can easily be corrected with T4 and the goitre is usually not of sufficient size to cause local symptoms. […] there is an association between this condition and thyroid lymphoma (rare, but risk by a factor of 70).”

“Hypothyroidism results from a variety of abnormalities that cause insufficient secretion of thyroid hormones […] The commonest cause is autoimmune thyroid disease. Myxoedema is severe hypothyroidism [which leads to] thickening of the facial features and a doughy induration of the skin. [The clinical picture of hypothyroidism:] *Insidious, non-specific onset. *Fatigue, lethargy, constipation, cold intolerance, muscle stiffness, cramps, carpal tunnel syndrome […] *Slowing of intellectual and motor activities. *↓ appetite and weight gain. *Dry skin; hair loss. […] [The term] [s]ubclinical hypothyroidism […] is used to denote raised TSH levels in the presence of normal concentrations of free thyroid hormones. *Treatment is indicated if the biochemistry is sustained in patients with a past history of radioiodine treatment for thyrotoxicosis or [positive] thyroid antibodies as, in these situations, progression to overt hypothyroidism is almost inevitable […] There is controversy over the advantages of T4 treatment in patients with [negative] thyroid antibodies and no previous radioiodine treatment. *If treatment is not given, follow-up with annual thyroid function tests is important. *There is no generally accepted consensus of when patients should receive treatment. […] *Thyroid hormone replacement with synthetic levothyroxine remains the treatment of choice in primary hypothyroidism. […] levothyroxine has a narrow therapeutic index […] Elevated TSH despite thyroxine replacement is common, most usually due to lack of compliance.”


January 8, 2018 Posted by | Books, Cancer/oncology, Diabetes, Medicine, Ophthalmology, Pharmacology | Leave a comment

Analgesia and Procedural Sedation

I didn’t actually like this lecture all that much, in part because I obviously disagree to some extent with the ideas expressed, but I try to remember to blog lectures I watch these days even if I don’t think they’re all that great. It’s a short lecture, but why not at least add a comment about urine drug screening and monitoring or patient selection/segmentation when you’re talking about patients whom you’re considering discharging with an opioid prescription? Recommending acupuncture in a pain management context? Etc.

Anyway, below a few links to stuff related to the coverage:

Pain Management in the Emergency Department.
WHO analgesic ladder.
Nonsteroidal anti-inflammatory drug.
Fentanyl (“This medication should not be used to treat pain other than chronic cancer pain, especially short-term pain such as migraines or other headaches, pain from an injury, or pain after a medical or dental procedure.” …to put it mildly, that’s not the impression you get from watching this lecture…)
Parenteral opioids in emergency medicine – A systematic review of efficacy and safety.
Procedural Sedation (medscape).

December 22, 2017 Posted by | Lectures, Medicine, Pharmacology | Leave a comment

A few diabetes papers of interest

i. Mechanisms and Management of Diabetic Painful Distal Symmetrical Polyneuropathy.

“Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15–20% of diabetic patients may have painful DSPN, but not all of these will require therapy. […] Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. […] All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment.”

“The neuropathies are the most common long-term microvascular complications of diabetes and affect those with both type 1 and type 2 diabetes, with up to 50% of older type 2 diabetic patients having evidence of a distal neuropathy (1). These neuropathies are characterized by a progressive loss of nerve fibers affecting both the autonomic and somatic divisions of the nervous system. The clinical features of the diabetic neuropathies vary immensely, and only a minority are associated with pain. The major portion of this review will be dedicated to the most common painful neuropathy, chronic sensorimotor distal symmetrical polyneuropathy (DSPN). This neuropathy has major detrimental effects on its sufferers, confirming an increased risk of foot ulceration and Charcot neuroarthropathy as well as being associated with increased mortality (1).

In addition to DSPN, other rarer neuropathies may also be associated with painful symptoms including acute painful neuropathy that often follows periods of unstable glycemic control, mononeuropathies (e.g., cranial nerve palsies), radiculopathies, and entrapment neuropathies (e.g., carpal tunnel syndrome). By far the most common presentation of diabetic polyneuropathy (over 90%) is typical DSPN or chronic DSPN. […] DSPN results in insensitivity of the feet that predisposes to foot ulceration (1) and/or neuropathic pain (painful DSPN), which can be disabling. […] The onset of DSPN is usually gradual or insidious and is heralded by sensory symptoms that start in the toes and then progress proximally to involve the feet and legs in a stocking distribution. When the disease is well established in the lower limbs in more severe cases, there is upper limb involvement, with a similar progression proximally starting in the fingers. As the disease advances further, motor manifestations, such as wasting of the small muscles of the hands and limb weakness, become apparent. In some cases, there may be sensory loss that the patient may not be aware of, and the first presentation may be a foot ulcer. Approximately 50% of patients with DSPN experience neuropathic symptoms in the lower limbs including uncomfortable tingling (dysesthesia), pain (burning; shooting or “electric-shock like”; lancinating or “knife-like”; “crawling”, or aching etc., in character), evoked pain (allodynia, hyperesthesia), or unusual sensations (such as a feeling of swelling of the feet or severe coldness of the legs when clearly the lower limbs look and feel fine, odd sensations on walking likened to “walking on pebbles” or “walking on hot sand,” etc.). There may be marked pain on walking that may limit exercise and lead to weight gain. Painful DSPN is characteristically more severe at night and often interferes with normal sleep (3). It also has a major impact on the ability to function normally (both mental and physical functioning, e.g., ability to maintain work, mood, and quality of life [QoL]) (3,4). […] The unremitting nature of the pain can be distressing, resulting in mood disorders including depression and anxiety (4). The natural history of painful DSPN has not been well studied […]. However, it is generally believed that painful symptoms may persist over the years (5), occasionally becoming less prominent as the sensory loss worsens (6).”

“There have been relatively few epidemiological studies that have specifically examined the prevalence of painful DSPN, which range from 10–26% (79). In a recent study of a large cohort of diabetic patients receiving community-based health care in northwest England (n = 15,692), painful DSPN assessed using neuropathy symptom and disability scores was found in 21% (7). In one population-based study from Liverpool, U.K., the prevalence of painful DSPN assessed by a structured questionnaire and examination was estimated at 16% (8). Notably, it was found that 12.5% of these patients had never reported their symptoms to their doctor and 39% had never received treatment for their pain (8), indicating that there may be considerable underdiagnosis and undertreatment of painful neuropathic symptoms compared with other aspects of diabetes management such as statin therapy and management of hypertension. Risk factors for DSPN per se have been extensively studied, and it is clear that apart from poor glycemic control, cardiovascular risk factors play a prominent role (10): risk factors for painful DSPN are less well known.”

“A broad spectrum of presentations may occur in patients with DSPN, ranging from one extreme of the patient with very severe painful symptoms but few signs, to the other when patients may present with a foot ulcer having lost all sensation without ever having any painful or uncomfortable symptoms […] it is well recognized that the severity of symptoms may not relate to the severity of the deficit on clinical examination (1). […] Because DSPN is a diagnosis of exclusion, a careful clinical history and a peripheral neurological and vascular examination of the lower limbs are essential to exclude other causes of neuropathic pain and leg/foot pain such as peripheral vascular disease, arthritis, malignancy, alcohol abuse, spinal canal stenosis, etc. […] Patients with asymmetrical symptoms and/or signs (such as loss of an ankle jerk in one leg only), rapid progression of symptoms, or predominance of motor symptoms and signs should be carefully assessed for other causes of the findings.”

“The fact that diabetes induces neuropathy and that in a proportion of patients this is accompanied by pain despite the loss of input and numbness, suggests that marked changes occur in the processes of pain signaling in the peripheral and central nervous system. Neuropathic pain is characterized by ongoing pain together with exaggerated responses to painful and nonpainful stimuli, hyperalgesia, and allodynia. […] the changes seen suggest altered peripheral signaling and central compensatory changes perhaps driven by the loss of input. […] Very clear evidence points to the key role of changes in ion channels as a consequence of nerve damage and their roles in the disordered activity and transduction in damaged and intact fibers (50). Sodium channels depolarize neurons and generate an action potential. Following damage to peripheral nerves, the normal distribution of these channels along a nerve is disrupted by the neuroma and “ectopic” activity results from the accumulation of sodium channels at or around the site of injury. Other changes in the distribution and levels of these channels are seen and impact upon the pattern of neuronal excitability in the nerve. Inherited pain disorders arise from mutated sodium channels […] and polymorphisms in this channel impact on the level of pain in patients, indicating that inherited differences in channel function might explain some of the variability in pain between patients with DSPN (53). […] Where sodium channels act to generate action potentials, potassium channels serve as the molecular brakes of excitable cells, playing an important role in modulating neuronal hyperexcitability. The drug retigabine, a potassium channel opener acting on the channel (KV7, M-current) opener, blunts behavioral hypersensitivity in neuropathic rats (56) and also inhibits C and Aδ-mediated responses in dorsal horn neurons in both naïve and neuropathic rats (57), but has yet to reach the clinic as an analgesic”.

and C fibers terminate primarily in the superficial laminae of the dorsal horn where the large majority of neurons are nociceptive specific […]. Some of these neurons gain low threshold inputs after neuropathy and these cells project predominantly to limbic brain areas […] spinal cord neurons provide parallel outputs to the affective and sensory areas of the brain. Changes induced in these neurons by repeated noxious inputs underpin central sensitization where the resultant hyperexcitability of neurons leads to greater responses to all subsequent inputs — innocuous and noxious — expanded receptive fields and enhanced outputs to higher levels of the brain […] As a consequence of these changes in the sending of nociceptive information within the peripheral nerve and then the spinal cord, the information sent to the brain becomes amplified so that pain ratings become higher. Alongside this, the persistent input into the limbic brain areas such as the amygdala are likely to be causal in the comorbidities that patients often report due to ongoing painful inputs disrupting normal function and generating fear, depression, and sleep problems […]. Of course, many patients report that their pains are worse at night, which may be due to nocturnal changes in these central pain processing areas. […] overall, the mechanisms of pain in diabetic neuropathy extend from altered channel function in peripheral nerves through enhanced spinal processing and finally to changes in many higher centers”.

Pharmacological treatment of painful DSPN is not entirely satisfactory because currently available drugs are often ineffective and complicated by adverse events. Tricyclic compounds (TCAs) have been used as first-line agents for many years, but their use is limited by frequent side effects that may be central or anticholinergic, including dry mouth, constipation, sweating, blurred vision, sedation, and orthostatic hypotension (with the risk of falls particularly in elderly patients). […] Higher doses have been associated with an increased risk of sudden cardiac death, and caution should be taken in any patient with a history of cardiovascular disease (65). […] The selective serotonin noradrenalin reuptake inhibitors (SNRI) duloxetine and venlafaxine have been used for the management of painful DSPN (65). […] there have been several clinical trials involving pregabalin in painful DSPN, and these showed clear efficacy in management of painful DSPN (69). […] The side effects include dizziness, somnolence, peripheral edema, headache, and weight gain.”

A major deficiency in the area of the treatment of neuropathic pain in diabetes is the relative lack of comparative or combination studies. Virtually all previous trials have been of active agents against placebo, whereas there is a need for more studies that compare a given drug with an active comparator and indeed lower-dose combination treatments (64). […] The European Federation of Neurological Societies proposed that first-line treatments might comprise of TCAs, SNRIs, gabapentin, or pregabalin (71). The U.K. National Institute for Health and Care Excellence guidelines on the management of neuropathic pain in nonspecialist settings proposed that duloxetine should be the first-line treatment with amitriptyline as an alternative, and pregabalin as a second-line treatment for painful DSPN (72). […] this recommendation of duloxetine as the first-line therapy was not based on efficacy but rather cost-effectiveness. More recently, the American Academy of Neurology recommended that pregabalin is “established as effective and should be offered for relief of [painful DSPN] (Level A evidence)” (73), whereas venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids, and capsaicin were considered to be “probably effective and should be considered for treatment of painful DSPN (Level B evidence)” (63). […] this recommendation was primarily based on achievement of greater than 80% completion rate of clinical trials, which in turn may be influenced by the length of the trials. […] the International Consensus Panel on Diabetic Neuropathy recommended TCAs, duloxetine, pregabalin, and gabapentin as first-line agents having carefully reviewed all the available literature regarding the pharmacological treatment of painful DSPN (65), the final drug choice tailored to the particular patient based on demographic profile and comorbidities. […] The initial selection of a particular first-line treatment will be influenced by the assessment of contraindications, evaluation of comorbidities […], and cost (65). […] caution is advised to start at lower than recommended doses and titrate gradually.”

ii. Sex Differences in All-Cause and Cardiovascular Mortality, Hospitalization for Individuals With and Without Diabetes, and Patients With Diabetes Diagnosed Early and Late.

“A challenge with type 2 diabetes is the late diagnosis of the disease because many individuals who meet the criteria are often asymptomatic. Approximately 183 million people, or half of those who have diabetes, are unaware they have the disease (1). Furthermore, type 2 diabetes can be present for 9 to 12 years before being diagnosed and, as a result, complications are often present at the time of diagnosis (3). […] Cardiovascular disease (CVD) is the most common comorbidity associated with diabetes, and with 50% of those with diabetes dying of CVD it is the most common cause of death (1). […] Newfoundland and Labrador has the highest age-standardized prevalence of diabetes in Canada (2), and the age-standardized mortality and hospitalization rates for CVD, AMI, and stroke are some of the highest in the country (21,22). A better understanding of mortality and hospitalizations associated with diabetes for males and females is important to support diabetes prevention and management. Therefore, the objectives of this study were to compare the risk of all-cause, CVD, AMI, and stroke mortality and hospitalizations for males and females with and without diabetes and those with early and late diagnoses of diabetes. […] We conducted a population-based retrospective cohort study including 73,783 individuals aged 25 years or older in Newfoundland and Labrador, Canada (15,152 with diabetes; 9,517 with late diagnoses). […] mean age at baseline was 60.1 years (SD, 14.3 years). […] Diabetes was classified as being diagnosed “early” and “late” depending on when diabetes-related comorbidities developed. Individuals early in the disease course would not have any diabetes-related comorbidities at the time of their case dates. On the contrary, a late-diagnosed diabetes patient would have comorbidities related to diabetes at the time of diagnosis.”

“For males, 20.5% (n = 7,751) had diabetes, whereas 20.6% (n = 7,401) of females had diabetes. […] Males and females with diabetes were more likely to die, to be younger at death, to have a shorter survival time, and to be admitted to the hospital than males and females without diabetes (P < 0.01). When admitted to the hospital, individuals with diabetes stayed longer than individuals without diabetes […] Both males and females with late diagnoses were significantly older at the time of diagnosis than those with early diagnoses […]. Males and females with late diagnoses of diabetes were more likely to be deceased at the end of the study period compared with those with early diagnoses […]. Those with early diagnoses were younger at death compared with those with late diagnoses (P < 0.01); however, median survival time for both males and females with early diagnoses was significantly longer than that of those with late diagnoses (P < 0.01). During the study period, males and females with late diabetes diagnoses were more likely to be hospitalized (P < 0.01) and have a longer length of hospital stay compared with those with early diagnoses (P < 0.01).”

“[T]he hospitalization results show that an early diagnosis […] increase the risk of all-cause, CVD, and AMI hospitalizations compared with individuals without diabetes. After adjusting for covariates, males with late diabetes diagnoses had an increased risk of all-cause and CVD mortality and hospitalizations compared with males without diabetes. Similar findings were found for females. A late diabetes diagnosis was positively associated with CVD mortality (HR 6.54 [95% CI 4.80–8.91]) and CVD hospitalizations (5.22 [4.31–6.33]) for females, and the risk was significantly higher compared with their male counterparts (3.44 [2.47–4.79] and 3.33 [2.80–3.95]).”

iii. Effect of Type 1 Diabetes on Carotid Structure and Function in Adolescents and Young Adults.

I may have discussed some of the results of this study before, but a search of the blog told me that I have not covered the study itself. I thought it couldn’t hurt to add a link and a few highlights here.

“Type 1 diabetes mellitus causes increased carotid intima-media thickness (IMT) in adults. We evaluated IMT in young subjects with type 1 diabetes. […] Participants with type 1 diabetes (N = 402) were matched to controls (N = 206) by age, sex, and race or ethnicity. Anthropometric and laboratory values, blood pressure, and IMT were measured.”

“Youth with type 1 diabetes had thicker bulb IMT, which remained significantly different after adjustment for demographics and cardiovascular risk factors. […] Because the rate of progression of IMT in healthy subjects (mean age, 40 years) in the Bogalusa Heart study was 0.017–0.020 mm/year (4), our difference of 0.016 mm suggests that our type 1 diabetic subjects had a vascular age 1 year advanced from their chronological age. […] adjustment for HbA1c ablated the case-control difference in IMT, suggesting that the thicker carotid IMT in the subjects with diabetes could be attributed to diabetes-related hyperglycemia.”

“In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, progression of IMT over the course of 6 years was faster in subjects with type 1 diabetes, yielding a thicker final IMT in cases (5). There was no difference in IMT at baseline. However, DCCT/EDIC did not image the bulb, which is likely the earliest site of thickening according to the Bogalusa Heart Study […] Our analyses reinforce the importance of imaging the carotid bulb, often the site of earliest detectible subclinical atherosclerosis in youth. The DCCT/EDIC study demonstrated that the intensive treatment group had a slower progression of IMT (5) and that mean HbA1c levels explained most of the differences in IMT progression between treatment groups (12). One longitudinal study of youth found children with type 1 diabetes who had progression of IMT over the course of 2 years had higher HbA1c (13). Our data emphasize the role of diabetes-related hyperglycemia in increasing IMT in youth with type 1 diabetes. […] In summary, our study provides novel evidence that carotid thickness is increased in youth with type 1 diabetes compared with healthy controls and that this difference is not accounted for by traditional cardiovascular risk factors. Better control of diabetes-related hyperglycemia may be needed to reduce future cardiovascular disease.”

iv. Factors Associated With Microalbuminuria in 7,549 Children and Adolescents With Type 1 Diabetes in the T1D Exchange Clinic Registry.

“Elevated urinary albumin excretion is an early sign of diabetic kidney disease (DKD). The American Diabetes Association (ADA) recommends screening for microalbuminuria (MA) annually in people with type 1 diabetes after 10 years of age and 5 years of diabetes duration, with a diagnosis of MA requiring two of three tests to be abnormal (1). Early diagnosis of MA is important because effective treatments exist to limit the progression of DKD (1). However, although reduced rates of MA have been reported over the past few decades in some (24) but not all (5,6) studies, it has been suggested that the development of proteinuria has not been prevented but, rather, has been delayed by ∼10 years and that further improvements in care are needed (7).

Limited data exist on the frequency of a clinical diagnosis of MA in the pediatric population with type 1 diabetes in the U.S. Our aim was to use the data from the T1D Exchange clinic registry to assess factors associated with MA in 7,549 children and adolescents with type 1 diabetes.”

“The analysis cohort included 7,549 participants, with mean age of 13.8 ± 3.5 years (range 2 to 19), mean age at type 1 diabetes onset of 6.9 ± 3.9 years, and mean diabetes duration of 6.5 ± 3.7 years; 49% were female. The racial/ethnic distribution was 78% non-Hispanic white, 6% non-Hispanic black, 10% Hispanic, and 5% other. The average of all HbA1c levels (for up to the past 13 years) was 8.4 ± 1.3% (69 ± 13.7 mmol/mol) […]. MA was present in 329 of 7,549 (4.4%) participants, with a higher frequency associated with longer diabetes duration, higher mean glycosylated hemoglobin (HbA1c) level, older age, female sex, higher diastolic blood pressure (BP), and lower BMI […] increasing age [was] mainly associated with an increase in the frequency of MA when HbA1c was ≥9.5% (≥80 mmol/mol). […] MA was uncommon (<2%) among participants with HbA1c <7.5% (<58 mmol/mol). Of those with MA, only 36% were receiving ACEI/ARB treatment. […] Our results provide strong support for prior literature in emphasizing the importance of good glycemic and BP control, particularly as diabetes duration increases, in order to reduce the risk of DKD.

v. Secular Changes in the Age-Specific Prevalence of Diabetes Among U.S. Adults: 1988–2010.

“This study included 22,586 adults sampled in three periods of the National Health and Nutrition Examination Survey (1988–1994, 1999–2004, and 2005–2010). Diabetes was defined as having self-reported diagnosed diabetes or having a fasting plasma glucose level ≥126 mg/dL or HbA1c ≥6.5% (48 mmol/mol). […] The number of adults with diabetes increased by 75% from 1988–1994 to 2005–2010. After adjusting for sex, race/ethnicity, and education level, the prevalence of diabetes increased over the two decades across all age-groups. Younger adults (20–34 years of age) had the lowest absolute increase in diabetes prevalence of 1.0%, followed by middle-aged adults (35–64) at 2.7% and older adults (≥65) at 10.0% (all P < 0.001). Comparing 2005–2010 with 1988–1994, the adjusted prevalence ratios (PRs) by age-group were 2.3, 1.3, and 1.5 for younger, middle-aged, and older adults, respectively (all P < 0.05). After additional adjustment for body mass index (BMI), waist-to-height ratio (WHtR), or waist circumference (WC), the adjusted PR remained statistically significant only for adults ≥65 years of age.

CONCLUSIONS During the past two decades, the prevalence of diabetes increased across all age-groups, but adults ≥65 years of age experienced the largest increase in absolute change. Obesity, as measured by BMI, WHtR, or WC, was strongly associated with the increase in diabetes prevalence, especially in adults <65.”

The crude prevalence of diabetes changed from 8.4% (95% CI 7.7–9.1%) in 1988–1994 to 12.1% (11.3–13.1%) in 2005–2010, with a relative increase of 44.8% (28.3–61.3%) between the two survey periods. There was less change of prevalence of undiagnosed diabetes (P = 0.053). […] The estimated number (in millions) of adults with diabetes grew from 14.9 (95% CI 13.3–16.4) in 1988–1994 to 26.1 (23.8–28.3) in 2005–2010, resulting in an increase of 11.2 prevalent cases (a 75.5% [52.1–98.9%] increase). Younger adults contributed 5.5% (2.5–8.4%), middle-aged adults contributed 52.9% (43.4–62.3%), and older adults contributed 41.7% (31.9–51.4%) of the increased number of cases. In each survey time period, the number of adults with diabetes increased with age until ∼60–69 years; thereafter, it decreased […] the largest increase of cases occurred in middle-aged and older adults.”

vi. The Expression of Inflammatory Genes Is Upregulated in Peripheral Blood of Patients With Type 1 Diabetes.

“Although much effort has been devoted toward discoveries with respect to gene expression profiling in human T1D in the last decade (15), previous studies had serious limitations. Microarray-based gene expression profiling is a powerful discovery platform, but the results must be validated by an alternative technique such as real-time RT-PCR. Unfortunately, few of the previous microarray studies on T1D have been followed by a validation study. Furthermore, most previous gene expression studies had small sample sizes (<100 subjects in each group) that are not adequate for the human population given the expectation of large expression variations among individual subjects. Finally, the selection of appropriate reference genes for normalization of quantitative real-time PCR has a major impact on data quality. Most of the previous studies have used only a single reference gene for normalization. Ideally, gene transcription studies using real-time PCR should begin with the selection of an appropriate set of reference genes to obtain more reliable results (68).

We have previously carried out extensive microarray analysis and identified >100 genes with significantly differential expression between T1D patients and control subjects. Most of these genes have important immunological functions and were found to be upregulated in autoantibody-positive subjects, suggesting their potential use as predictive markers and involvement in T1D development (2). In this study, real-time RT-PCR was performed to validate a subset of the differentially expressed genes in a large sample set of 928 T1D patients and 922 control subjects. In addition to the verification of the gene expression associated with T1D, we also identified genes with significant expression changes in T1D patients with diabetes complications.

“Of the 18 genes analyzed here, eight genes […] had higher expression and three genes […] had lower expression in T1D patients compared with control subjects, indicating that genes involved in inflammation, immune regulation, and antigen processing and presentation are significantly altered in PBMCs from T1D patients. Furthermore, one adhesion molecule […] and three inflammatory genes mainly expressed by myeloid cells […] were significantly higher in T1D patients with complications (odds ratio [OR] 1.3–2.6, adjusted P value = 0.005–10−8), especially those patients with neuropathy (OR 4.8–7.9, adjusted P value <0.005). […] These findings suggest that inflammatory mediators secreted mainly by myeloid cells are implicated in T1D and its complications.

vii. Overexpression of Hemopexin in the Diabetic Eye – A new pathogenic candidate for diabetic macular edema.

“Diabetic retinopathy remains the leading cause of preventable blindness among working-age individuals in developed countries (1). Whereas proliferative diabetic retinopathy (PDR) is the commonest sight-threatening lesion in type 1 diabetes, diabetic macular edema (DME) is the primary cause of poor visual acuity in type 2 diabetes. Because of the high prevalence of type 2 diabetes, DME is the main cause of visual impairment in diabetic patients (2). When clinically significant DME appears, laser photocoagulation is currently indicated. However, the optimal period of laser treatment is frequently passed and, moreover, is not uniformly successful in halting visual decline. In addition, photocoagulation is not without side effects, with visual field loss and impairment of either adaptation or color vision being the most frequent. Intravitreal corticosteroids have been successfully used in eyes with persistent DME and loss of vision after the failure of conventional treatment. However, reinjections are commonly needed, and there are substantial adverse effects such as infection, glaucoma, and cataract formation. Intravitreal anti–vascular endothelial growth factor (VEGF) agents have also found an improvement of visual acuity and decrease of retinal thickness in DME, even in nonresponders to conventional treatment (3). However, apart from local side effects such as endophthalmitis and retinal detachment, the response to treatment of DME by VEGF blockade is not prolonged and is subject to significant variability. For all these reasons, new pharmacological treatments based on the understanding of the pathophysiological mechanisms of DME are needed.”

“Vascular leakage due to the breakdown of the blood-retinal barrier (BRB) is the main event involved in the pathogenesis of DME (4). However, little is known regarding the molecules primarily involved in this event. By means of a proteomic analysis, we have found that hemopexin was significantly increased in the vitreous fluid of patients with DME in comparison with PDR and nondiabetic control subjects (5). Hemopexin is the best characterized permeability factor in steroid-sensitive nephrotic syndrome (6,7). […] T cell–associated cytokines like tumor necrosis factor-α are able to enhance hemopexin production in mesangial cells in vitro, and this effect is prevented by corticosteroids (8). However, whether hemopexin also acts as a permeability factor in the BRB and its potential response to corticosteroids remains to be elucidated. […] the aims of the current study were 1) to compare hemopexin and hemopexin receptor (LDL receptor–related protein [LRP1]) levels in retina and in vitreous fluid from diabetic and nondiabetic patients, 2) to evaluate the effect of hemopexin on the permeability of outer and inner BRB in cell cultures, and 3) to determine whether anti-hemopexin antibodies and dexamethasone were able to prevent an eventual hemopexin-induced hyperpermeability.”

“In the current study, we […] confirmed our previous results obtained by a proteomic approach showing that hemopexin is higher in the vitreous fluid of diabetic patients with DME in comparison with diabetic patients with PDR and nondiabetic subjects. In addition, we provide the first evidence that hemopexin is overexpressed in diabetic eye. Furthermore, we have shown that hemopexin leads to the disruption of RPE [retinal pigment epithelium] cells, thus increasing permeability, and that this effect is prevented by dexamethasone. […] Our findings suggest that hemopexin can be considered a new candidate in the pathogenesis of DME and a new therapeutic target.”

viii. Relationship Between Overweight and Obesity With Hospitalization for Heart Failure in 20,985 Patients With Type 1 Diabetes.

“We studied patients with type 1 diabetes included in the Swedish National Diabetes Registry during 1998–2003, and they were followed up until hospitalization for HF, death, or 31 December 2009. Cox regression was used to estimate relative risks. […] Type 1 diabetes is defined in the NDR as receiving treatment with insulin only and onset at age 30 years or younger. These characteristics previously have been validated as accurate in 97% of cases (11). […] In a sample of 20,985 type 1 diabetic patients (mean age, 38.6 years; mean BMI, 25.0 kg/m2), 635 patients […] (3%) were admitted for a primary or secondary diagnosis of HF during a median follow-up of 9 years, with an incidence of 3.38 events per 1,000 patient-years (95% CI, 3.12–3.65). […] Cox regression adjusting for age, sex, diabetes duration, smoking, HbA1c, systolic and diastolic blood pressures, and baseline and intercurrent comorbidities (including myocardial infarction) showed a significant relationship between BMI and hospitalization for HF (P < 0.0001). In reference to patients in the BMI 20–25 kg/m2 category, hazard ratios (HRs) were as follows: HR 1.22 (95% CI, 0.83–1.78) for BMI <20 kg/m2; HR 0.94 (95% CI, 0.78–1.12) for BMI 25–30 kg/m2; HR 1.55 (95% CI, 1.20–1.99) for BMI 30–35 kg/m2; and HR 2.90 (95% CI, 1.92–4.37) for BMI ≥35 kg/m2.

CONCLUSIONS Obesity, particularly severe obesity, is strongly associated with hospitalization for HF in patients with type 1 diabetes, whereas no similar relation was present in overweight and low body weight.”

“In contrast to type 2 diabetes, obesity is not implicated as a causal factor in type 1 diabetes and maintaining normal weight is accordingly less of a focus in clinical practice of patients with type 1 diabetes. Because most patients with type 2 diabetes are overweight or obese and glucose levels can normalize in some patients after weight reduction, this is usually an important part of integrated diabetes care. Our findings indicate that given the substantial risk of cardiovascular disease in type 1 diabetic patients, it is crucial for clinicians to also address weight issues in type 1 diabetes. Because many patients are normal weight when diabetes is diagnosed, careful monitoring of weight with a view to maintaining normal weight is probably more essential than previously thought. Although overweight was not associated with an increased risk of HF, higher BMI levels probably increase the risk of future obesity. Our finding that 71% of patients with BMI >35 kg/m2 were women is potentially important, although this should be tested in other populations given that it could be a random finding. If not random, especially because the proportion was much higher than in the entire cohort (45%), then it may indicate that severe obesity is a greater problem in women than in men with type 1 diabetes.”

November 30, 2017 Posted by | Cardiology, Diabetes, Genetics, Nephrology, Neurology, Ophthalmology, Pharmacology, Studies | Leave a comment

A few diabetes papers of interest

i. Thirty Years of Research on the Dawn Phenomenon: Lessons to Optimize Blood Glucose Control in Diabetes.

“More than 30 years ago in Diabetes Care, Schmidt et al. (1) defined “dawn phenomenon,” the night-to-morning elevation of blood glucose (BG) before and, to a larger extent, after breakfast in subjects with type 1 diabetes (T1D). Shortly after, a similar observation was made in type 2 diabetes (T2D) (2), and the physiology of glucose homeostasis at night was studied in normal, nondiabetic subjects (35). Ever since the first description, the dawn phenomenon has been studied extensively with at least 187 articles published as of today (6). […] what have we learned from the last 30 years of research on the dawn phenomenon? What is the appropriate definition, the identified mechanism(s), the importance (if any), and the treatment of the dawn phenomenon in T1D and T2D?”

“Physiology of glucose homeostasis in normal, nondiabetic subjects indicates that BG and plasma insulin concentrations remain remarkably flat and constant overnight, with a modest, transient increase in insulin secretion just before dawn (3,4) to restrain hepatic glucose production (4) and prevent hyperglycemia. Thus, normal subjects do not exhibit the dawn phenomenon sensu strictiori because they secrete insulin to prevent it.

In T1D, the magnitude of BG elevation at dawn first reported was impressive and largely secondary to the decrease of plasma insulin concentration overnight (1), commonly observed with evening administration of NPH or lente insulins (8) (Fig. 1). Even in early studies with intravenous insulin by the “artificial pancreas” (Biostator) (2), plasma insulin decreased overnight because of progressive inactivation of insulin in the pump (9). This artifact exaggerated the dawn phenomenon, now defined as need for insulin to limit fasting hyperglycemia (2). When the overnight waning of insulin was prevented by continuous subcutaneous insulin infusion (CSII) […] or by the long-acting insulin analogs (LA-IAs) (8), it was possible to quantify the real magnitude of the dawn phenomenon — 15–25 mg/dL BG elevation from nocturnal nadir to before breakfast […]. Nocturnal spikes of growth hormone secretion are the most likely mechanism of the dawn phenomenon in T1D (13,14). The observation from early pioneering studies in T1D (1012) that insulin sensitivity is higher after midnight until 3 a.m. as compared to the period 4–8 a.m., soon translated into use of more physiological replacement of basal insulin […] to reduce risk of nocturnal hypoglycemia while targeting fasting near-normoglycemia”.

“In T2D, identification of diurnal changes in BG goes back decades, but only quite recently fasting hyperglycemia has been attributed to a transient increase in hepatic glucose production (both glycogenolysis and gluconeogenesis) at dawn in the absence of compensatory insulin secretion (1517). Monnier et al. (7) report on the overnight (interstitial) glucose concentration (IG), as measured by continuous ambulatory IG monitoring, in three groups of 248 subjects with T2D […] Importantly, the dawn phenomenon had an impact on mean daily IG and A1C (mean increase of 0.39% [4.3 mmol/mol]), which was independent of treatment. […] Two messages from the data of Monnier et al. (7) are important. First, the dawn phenomenon is confirmed as a frequent event across the heterogeneous population of T2D independent of (oral) treatment and studied in everyday life conditions, not only in the setting of specialized clinical research units. Second, the article reaffirms that the primary target of treatment in T2D is to reestablish near-normoglycemia before and after breakfast (i.e., to treat the dawn phenomenon) to lower mean daily BG and A1C (8). […] the dawn phenomenon induces hyperglycemia not only before, but, to a larger extent, after breakfast as well (7,18). Over the years, fasting (and postbreakfast) hyperglycemia in T2D worsens as result of progressively impaired pancreatic B-cell function on the background of continued insulin resistance primarily at dawn (8,1518) and independently of age (19). Because it is an early metabolic abnormality leading over time to the vicious circle of “hyperglycemia begets hyperglycemia” by glucotoxicity and lipotoxicity, the dawn phenomenon in T2D should be treated early and appropriately before A1C continues to increase (20).”

“Oral medications do not adequately control the dawn phenomenon, even when given in combination (7,18). […] The evening replacement of basal insulin, which abolishes the dawn phenomenon by restraining hepatic glucose production and lipolysis (21), is an effective treatment as it mimics the physiology of glucose homeostasis in normal, nondiabetic subjects (4). Early use of basal insulin in T2D is an add-on option treatment after failure of metformin to control A1C <7.0% (20). However, […] it would be wise to consider initiation of basal insulin […] before — not after — A1C has increased well beyond 7.0%, as usually it is done in practice currently.”

ii. Peripheral Neuropathy in Adolescents and Young Adults With Type 1 and Type 2 Diabetes From the SEARCH for Diabetes in Youth Follow-up Cohort.

“Diabetic peripheral neuropathy (DPN) is among the most distressing of all the chronic complications of diabetes and is a cause of significant disability and poor quality of life (4). Depending on the patient population and diagnostic criteria, the prevalence of DPN among adults with diabetes ranges from 30 to 70% (57). However, there are insufficient data on the prevalence and predictors of DPN among the pediatric population. Furthermore, early detection and good glycemic control have been proven to prevent or delay adverse outcomes associated with DPN (5,8,9). Near-normal control of blood glucose beginning as soon as possible after the onset of diabetes may delay the development of clinically significant nerve impairment (8,9). […] The American Diabetes Association (ADA) recommends screening for DPN in children and adolescents with type 2 diabetes at diagnosis and 5 years after diagnosis for those with type 1 diabetes, followed by annual evaluations thereafter, using simple clinical tests (10). Since subclinical signs of DPN may precede development of frank neuropathic symptoms, systematic, preemptive screening is required in order to identify DPN in its earliest stages.

There are various measures that can be used for the assessment of DPN. The Michigan Neuropathy Screening Instrument (MNSI) is a simple, sensitive, and specific tool for the screening of DPN (11). It was validated in large independent cohorts (12,13) and has been widely used in clinical trials and longitudinal cohort studies […] The aim of this pilot study was to provide preliminary estimates of the prevalence of and factors associated with DPN among children and adolescents with type 1 and type 2 diabetes.”

“A total of 399 youth (329 with type 1 and 70 with type 2 diabetes) participated in the pilot study. Youth with type 1 diabetes were younger (mean age 15.7 ± 4.3 years) and had a shorter duration of diabetes (mean duration 6.2 ± 0.9 years) compared with youth with type 2 diabetes (mean age 21.6 ± 4.1 years and mean duration 7.6 ± 1.8 years). Participants with type 2 diabetes had a higher BMI z score and waist circumference, were more likely to be smokers, and had higher blood pressure and lipid levels than youth with type 1 diabetes (all P < 0.001). A1C, however, did not significantly differ between the two groups (mean A1C 8.8 ± 1.8% [73 ± 2 mmol/mol] for type 1 diabetes and 8.5 ± 2.9% [72 ± 3 mmol/mol] for type 2 diabetes; P = 0.5) but was higher than that recommended by the ADA for this age-group (A1C ≤7.5%) (10). The prevalence of DPN (defined as the MNSIE score >2) was 8.2% among youth with type 1 diabetes and 25.7% among those with type 2 diabetes. […] Youth with DPN were older and had a longer duration of diabetes, greater central obesity (increased waist circumference), higher blood pressure, an atherogenic lipid profile (low HDL cholesterol and marginally high triglycerides), and microalbuminuria. A1C […] was not significantly different between those with and without DPN (9.0% ± 2.0 […] vs. 8.8% ± 2.1 […], P = 0.58). Although nearly 37% of youth with type 2 diabetes came from lower-income families with annual income <25,000 USD per annum (as opposed to 11% for type 1 diabetes), socioeconomic status was not significantly associated with DPN (P = 0.77).”

“In the unadjusted logistic regression model, the odds of having DPN was nearly four times higher among those with type 2 diabetes compared with youth with type 1 diabetes (odds ratio [OR] 3.8 [95% CI 1.9–7.5, P < 0.0001). This association was attenuated, but remained significant, after adjustment for age and sex (OR 2.3 [95% CI 1.1–5.0], P = 0.03). However, this association was no longer significant (OR 2.1 [95% CI 0.3–15.9], P = 0.47) when additional covariates […] were added to the model […] The loss of the association between diabetes type and DPN with addition of covariates in the fully adjusted model could be due to power loss, given the small number of youth with DPN in the sample, or indicative of stronger associations between these covariates and DPN such that conditioning on them eliminates the observed association between DPN and diabetes type.”

“The prevalence of DPN among type 1 diabetes youth in our pilot study is lower than that reported by Eppens et al. (15) among 1,433 Australian adolescents with type 1 diabetes assessed by thermal threshold testing and VPT (prevalence of DPN 27%; median age and duration 15.7 and 6.8 years, respectively). A much higher prevalence was also reported among Danish (62.5%) and Brazilian (46%) cohorts of type 1 diabetes youth (16,17) despite a younger age (mean age among Danish children 13.7 years and Brazilian cohort 12.9 years). The prevalence of DPN among youth with type 2 diabetes (26%) found in our study is comparable to that reported among the Australian cohort (21%) (15). The wide ranges in the prevalence estimates of DPN among the young cannot solely be attributed to the inherent racial/ethnic differences in this population but could potentially be due to the differing criteria and diagnostic tests used to define and characterize DPN.”

“In our study, the duration of diabetes was significantly longer among those with DPN, but A1C values did not differ significantly between the two groups, suggesting that a longer duration with its sustained impact on peripheral nerves is an important determinant of DPN. […] Cho et al. (22) reported an increase in the prevalence of DPN from 14 to 28% over 17 years among 819 Australian adolescents with type 1 diabetes aged 11–17 years at baseline, despite improvements in care and minor improvements in A1C (8.2–8.7%). The prospective Danish Study Group of Diabetes in Childhood also found no association between DPN (assessed by VPT) and glycemic control (23).”

“In conclusion, our pilot study found evidence that the prevalence of DPN in adolescents with type 2 diabetes approaches rates reported in adults with diabetes. Several CVD risk factors such as central obesity, elevated blood pressure, dyslipidemia, and microalbuminuria, previously identified as predictors of DPN among adults with diabetes, emerged as independent predictors of DPN in this young cohort and likely accounted for the increased prevalence of DPN in youth with type 2 diabetes.

iii. Disturbed Eating Behavior and Omission of Insulin in Adolescents Receiving Intensified Insulin Treatment.

“Type 1 diabetes appears to be a risk factor for the development of disturbed eating behavior (DEB) (1,2). Estimates of the prevalence of DEB among individuals with type 1 diabetes range from 10 to 49% (3,4), depending on methodological issues such as the definition and measurement of DEB. Some studies only report the prevalence of full-threshold diagnoses of anorexia nervosa, bulimia nervosa, and eating disorders not otherwise specified, whereas others also include subclinical eating disorders (1). […] Although different terminology complicates the interpretation of prevalence rates across studies, the findings are sufficiently robust to indicate that there is a higher prevalence of DEB in type 1 diabetes compared with healthy controls. A meta-analysis reported a three-fold increase of bulimia nervosa, a two-fold increase of eating disorders not otherwise specified, and a two-fold increase of subclinical eating disorders in patients with type 1 diabetes compared with controls (2). No elevated rates of anorexia nervosa were found.”

“When DEB and type 1 diabetes co-occur, rates of morbidity and mortality are dramatically increased. A Danish study of comorbid type 1 diabetes and anorexia nervosa showed that the crude mortality rate at 10-year follow-up was 2.5% for type 1 diabetes and 6.5% for anorexia nervosa, but the rate increased to 34.8% when occurring together (the standardized mortality rates were 4.06, 8.86, and 14.5, respectively) (9). The presence of DEB in general also can severely impair metabolic control and advance the onset of long-term diabetes complications (4). Insulin reduction or omission is an efficient weight loss strategy uniquely available to patients with type 1 diabetes and has been reported in up to 37% of patients (1012). Insulin restriction is associated with poorer metabolic control, and previous research has found that self-reported insulin restriction at baseline leads to a three-fold increased risk of mortality at 11-year follow-up (10).

Few population-based studies have specifically investigated the prevalence of and relationship between DEBs and insulin restriction. The generalizability of existing research remains limited by relatively small samples and a lack of males. Further, many studies have relied on generic measures of DEBs, which may not be appropriate for use in individuals with type 1 diabetes. The Diabetes Eating Problem Survey–Revised (DEPS-R) is a newly developed and diabetes-specific screening tool for DEBs. A recent study demonstrated satisfactory psychometric properties of the Norwegian version of the DEPS-R among children and adolescents with type 1 diabetes 11–19 years of age (13). […] This study aimed to assess young patients with type 1 diabetes to assess the prevalence of DEBs and frequency of insulin omission or restriction, to compare the prevalence of DEB between males and females across different categories of weight and age, and to compare the clinical features of participants with and without DEBs and participants who restrict and do not restrict insulin. […] The final sample consisted of 770 […] children and adolescents with type 1 diabetes 11–19 years of age. There were 380 (49.4%) males and 390 (50.6%) females.”

27.7% of female and 9% of male children and adolescents with type 1 diabetes receiving intensified insulin treatment scored above the predetermined cutoff on the DEPS-R, suggesting a level of disturbed eating that warrants further attention by treatment providers. […] Significant differences emerged across age and weight categories, and notable sex-specific trends were observed. […] For the youngest (11–13 years) and underweight (BMI <18.5) categories, the proportion of DEB was <10% for both sexes […]. Among females, the prevalence of DEB increased dramatically with age to ∼33% among 14 to 16 year olds and to nearly 50% among 17 to 19 year olds. Among males, the rate remained low at 7% for 14 to 16 year olds and doubled to ∼15% for 17 to 19 year olds.

A similar sex-specific pattern was detected across weight categories. Among females, the prevalence of DEB increased steadily and significantly from 9% among the underweight category to 23% for normal weight, 42% for overweight, and 53% for the obese categories, respectively. Among males, ∼6–7% of both the underweight and normal weight groups reported DEB, with rates increasing to ∼15% for both the overweight and obese groups. […] When separated by sex, females scoring above the cutoff on the DEPS-R had significantly higher HbA1c (9.2% [SD, 1.9]) than females scoring below the cutoff (8.4% [SD, 1.3]; P < 0.001). The same trend was observed among males (9.2% [SD, 1.6] vs. 8.4% [SD, 1.3]; P < 0.01). […] A total of 31.6% of the participants reported using less insulin and 6.9% reported skipping their insulin dose entirely at least occasionally after overeating. When assessing the sexes separately, we found that 36.8% of females reported restricting and 26.2% reported skipping insulin because of overeating. The rates for males were 9.4 and 4.5%, respectively.”

“The finding that DEBs are common in young patients with type 1 diabetes is in line with previous literature (2). However, because of different assessment methods and different definitions of DEB, direct comparison with other studies is complicated, especially because this is the first study to have used the DEPS-R in a prevalence study. However, two studies using the original DEPS have reported similar results, with 37.9% (23) and 53.8% (24) of the participants reporting engaging in unhealthy weight control practices. In our study, females scored significantly higher than males, which is not surprising given previous studies demonstrating an increased risk of development of DEB in nondiabetic females compared with males. In addition, the prevalence rates increased considerably by increasing age and weight. A relationship between eating pathology and older age and higher BMI also has been demonstrated in previous research conducted in both diabetic and nondiabetic adolescent populations.”

“Consistent with existent literature (1012,27), we found a high frequency of insulin restriction. For example, Bryden et al. (11) assessed 113 males and females (aged 17–25 years) with type 1 diabetes and found that a total of 37% of the females (no males) reported a history of insulin omission or reduction for weight control purposes. Peveler et al. (12) investigated 87 females with type 1 diabetes aged 11–25 years, and 36% reported intentionally reducing or omitting their insulin doses to control their weight. Finally, Goebel-Fabbri et al. (10) examined 234 females 13–60 years of age and found that 30% reported insulin restriction. Similarly, 36.8% of the participants in our study reported reducing their insulin doses occasionally or more often after overeating.”

iv. Clinical Inertia in People With Type 2 Diabetes. A retrospective cohort study of more than 80,000 people.

“Despite good-quality evidence of tight glycemic control, particularly early in the disease trajectory (3), people with type 2 diabetes often do not reach recommended glycemic targets. Baseline characteristics in observational studies indicate that both insulin-experienced and insulin-naïve people may have mean HbA1c above the recommended target levels, reflecting the existence of patients with poor glycemic control in routine clinical care (810). […] U.K. data, based on an analysis reflecting previous NICE guidelines, show that it takes a mean of 7.7 years to initiate insulin after the start of the last OAD [oral antidiabetes drugs] (in people taking two or more OADs) and that mean HbA1c is ~10% (86 mmol/mol) at the time of insulin initiation (12). […] This failure to intensify treatment in a timely manner has been termed clinical inertia; however, data are lacking on clinical inertia in the diabetes-management pathway in a real-world primary care setting, and studies that have been carried out are, relatively speaking, small in scale (13,14). This retrospective cohort analysis investigates time to intensification of treatment in people with type 2 diabetes treated with OADs and the associated levels of glycemic control, and compares these findings with recommended treatment guidelines for diabetes.”

“We used the Clinical Practice Research Datalink (CPRD) database. This is the world’s largest computerized database, representing the primary care longitudinal records of >13 million patients from across the U.K. The CPRD is representative of the U.K. general population, with age and sex distributions comparable with those reported by the U.K. National Population Census (15). All information collected in the CPRD has been subjected to validation studies and been proven to contain consistent and high-quality data (16).”

“50,476 people taking one OAD, 25,600 people taking two OADs, and 5,677 people taking three OADs were analyzed. Mean baseline HbA1c (the most recent measurement within 6 months before starting OADs) was 8.4% (68 mmol/mol), 8.8% (73 mmol/mol), and 9.0% (75 mmol/mol) in people taking one, two, or three OADs, respectively. […] In people with HbA1c ≥7.0% (≥53 mmol/mol) taking one OAD, median time to intensification with an additional OAD was 2.9 years, whereas median time to intensification with insulin was >7.2 years. Median time to insulin intensification in people with HbA1c ≥7.0% (≥53 mmol/mol) taking two or three OADs was >7.2 and >7.1 years, respectively. In people with HbA1c ≥7.5% or ≥8.0% (≥58 or ≥64 mmol/mol) taking one OAD, median time to intensification with an additional OAD was 1.9 or 1.6 years, respectively; median time to intensification with insulin was >7.1 or >6.9 years, respectively. In those people with HbA1c ≥7.5% or ≥8.0% (≥58 or ≥64 mmol/mol) and taking two OADs, median time to insulin was >7.2 and >6.9 years, respectively; and in those people taking three OADs, median time to insulin intensification was >6.1 and >6.0 years, respectively.”

“By end of follow-up, treatment of 17.5% of people with HbA1c ≥7.0% (≥53 mmol/mol) taking three OADs was intensified with insulin, treatment of 20.6% of people with HbA1c ≥7.5% (≥58 mmol/mol) taking three OADs was intensified with insulin, and treatment of 22.0% of people with HbA1c ≥8.0% (≥64 mmol/mol) taking three OADs was intensified with insulin. There were minimal differences in the proportion of patients intensified between the groups. […] In people taking one OAD, the probability of an additional OAD or initiation of insulin was 23.9% after 1 year, increasing to 48.7% by end of follow-up; in people taking two OADs, the probability of an additional OAD or initiation of insulin was 11.4% after 1 year, increasing to 30.1% after 2 years; and in people taking three OADs, the probability of an additional OAD or initiation of insulin was 5.7% after 1 year, increasing to 12.0% by the end of follow-up […] Mean ± SD HbA1c in patients taking one OAD was 8.7 ± 1.6% in those intensified with an additional OAD (n = 14,605), 9.4 ± 2.3% (n = 1,228) in those intensified with insulin, and 8.7 ± 1.7% (n = 15,833) in those intensified with additional OAD or insulin. Mean HbA1c in patients taking two OADs was 8.8 ± 1.5% (n = 3,744), 9.8 ± 1.9% (n = 1,631), and 9.1 ± 1.7% (n = 5,405), respectively. In patients taking three OADs, mean HbA1c at intensification with insulin was 9.7 ± 1.6% (n = 514).”

This analysis shows that there is a delay in intensifying treatment in people with type 2 diabetes with suboptimal glycemic control, with patients remaining in poor glycemic control for >7 years before intensification of treatment with insulin. In patients taking one, two, or three OADs, median time from initiation of treatment to intensification with an additional OAD for any patient exceeded the maximum follow-up time of 7.2–7.3 years, dependent on subcohort. […] Despite having HbA1c levels for which diabetes guidelines recommend treatment intensification, few people appeared to undergo intensification (4,6,7). The highest proportion of people with clinical inertia was for insulin initiation in people taking three OADs. Consequently, these people experienced prolonged periods in poor glycemic control, which is detrimental to long-term outcomes.”

“Previous studies in U.K. general practice have shown similar findings. A retrospective study involving 14,824 people with type 2 diabetes from 154 general practice centers contributing to the Doctors Independent Network Database (DIN-LINK) between 1995 and 2005 observed that median time to insulin initiation for people prescribed multiple OADs was 7.7 years (95% CI 7.4–8.5 years); mean HbA1c before insulin was 9.85% (84 mmol/mol), which decreased by 1.34% (95% CI 1.24–1.44%) after therapy (12). A longitudinal observational study from health maintenance organization data in 3,891 patients with type 2 diabetes in the U.S. observed that, despite continued HbA1c levels >7% (>53 mmol/mol), people treated with sulfonylurea and metformin did not start insulin for almost 3 years (21). Another retrospective cohort study, using data from the Health Improvement Network database of 2,501 people with type 2 diabetes, estimated that only 25% of people started insulin within 1.8 years of multiple OAD failure, if followed for 5 years, and that 50% of people delayed starting insulin for almost 5 years after failure of glycemic control with multiple OADs (22). The U.K. cohort of a recent, 26-week observational study examining insulin initiation in clinical practice reported a large proportion of insulin-naïve people with HbA1c >9% (>75 mmol/mol) at baseline (64%); the mean HbA1c in the global cohort was 8.9% (74 mmol/mol) (10). Consequently, our analysis supports previous findings concerning clinical inertia in both U.K. and U.S. general practice and reflects little improvement in recent years, despite updated treatment guidelines recommending tight glycemic control.

v. Small- and Large-Fiber Neuropathy After 40 Years of Type 1 Diabetes. Associations with glycemic control and advanced protein glycation: the Oslo Study.

“How hyperglycemia may cause damage to the nervous system is not fully understood. One consequence of hyperglycemia is the generation of advanced glycation end products (AGEs) that can form nonenzymatically between glucose, lipids, and amino groups. It is believed that AGEs are involved in the pathophysiology of neuropathy. AGEs tend to affect cellular function by altering protein function (11). One of the AGEs, N-ε-(carboxymethyl)lysine (CML), has been found in excessive amounts in the human diabetic peripheral nerve (12). High levels of methylglyoxal in serum have been found to be associated with painful peripheral neuropathy (13). In recent years, differentiation of affected nerves is possible by virtue of specific function tests to distinguish which fibers are damaged in diabetic polyneuropathy: large myelinated (Aα, Aβ), small thinly myelinated (Aδ), or small nonmyelinated (C) fibers. […] Our aims were to evaluate large- and small-nerve fiber function in long-term type 1 diabetes and to search for longitudinal associations with HbA1c and the AGEs CML and methylglyoxal-derived hydroimidazolone.”

“27 persons with type 1 diabetes of 40 ± 3 years duration underwent large-nerve fiber examinations, with nerve conduction studies at baseline and years 8, 17, and 27. Small-fiber functions were assessed by quantitative sensory thresholds (QST) and intraepidermal nerve fiber density (IENFD) at year 27. HbA1c was measured prospectively through 27 years. […] Fourteen patients (52%) reported sensory symptoms. Nine patients reported symptoms of a sensory neuropathy (reduced sensibility in feet or impaired balance), while three of these patients described pain. Five patients had symptoms compatible with carpal tunnel syndrome (pain or paresthesias within the innervation territory of the median nerve […]. An additional two had no symptoms but abnormal neurological tests with absent tendon reflexes and reduced sensibility. A total of 16 (59%) of the patients had symptoms or signs of neuropathy. […] No patient with symptoms of neuropathy had normal neurophysiological findings. […] Abnormal autonomic testing was observed in 7 (26%) of the patients and occurred together with neurophysiological signs of peripheral neuropathy. […] Twenty-two (81%) had small-fiber dysfunction by QST. Heat pain thresholds in the foot were associated with hydroimidazolone and HbA1c. IENFD was abnormal in 19 (70%) and significantly lower in diabetic patients than in age-matched control subjects (4.3 ± 2.3 vs. 11.2 ± 3.5 mm, P < 0.001). IENFD correlated negatively with HbA1c over 27 years (r = −0.4, P = 0.04) and CML (r = −0.5, P = 0.01). After adjustment for age, height, and BMI in a multiple linear regression model, CML was still independently associated with IENFD.”

Our study shows that small-fiber dysfunction is more prevalent than large-fiber dysfunction in diabetic neuropathy after long duration of type 1 diabetes. Although large-fiber abnormalities were less common than small-fiber abnormalities, almost 60% of the participants had their large nerves affected after 40 years with diabetes. Long-term blood glucose estimated by HbA1c measured prospectively through 27 years and AGEs predict large- and small-nerve fiber function.”

vi. Subarachnoid Hemorrhage in Type 1 Diabetes. A prospective cohort study of 4,083 patients with diabetes.

“Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular event, which is usually caused by a rupture of a cerebrovascular aneurysm. These aneurysms are mostly found in relatively large-caliber (≥1 mm) vessels and can often be considered as macrovascular lesions. The overall incidence of SAH has been reported to be 10.3 per 100,000 person-years (1), even though the variation in incidence between countries is substantial (1). Notably, the population-based incidence of SAH is 35 per 100,000 person-years in the adult (≥25 years of age) Finnish population (2). The incidence of nonaneurysmal SAH is globally unknown, but it is commonly believed that 5–15% of all SAHs are of nonaneurysmal origin. Prospective, long-term, population-based SAH risk factor studies suggest that smoking (24), high blood pressure (24), age (2,3), and female sex (2,4) are the most important risk factors for SAH, whereas diabetes (both types 1 and 2) does not appear to be associated with an increased risk of SAH (2,3).

An increased risk of cardiovascular disease is well recognized in people with diabetes. There are, however, very few studies on the risk of cerebrovascular disease in type 1 diabetes since most studies have focused on type 2 diabetes alone or together with type 1 diabetes. Cerebrovascular mortality in the 20–39-year age-group of people with type 1 diabetes is increased five- to sevenfold in comparison with the general population but accounts only for 15% of all cardiovascular deaths (5). Of the cerebrovascular deaths in patients with type 1 diabetes, 23% are due to hemorrhagic strokes (5). However, the incidence of SAH in type 1 diabetes is unknown. […] In this prospective cohort study of 4,083 patients with type 1 diabetes, we aimed to determine the incidence and characteristics of SAH.”

“52% [of participants] were men, the mean age was 37.4 ± 11.8 years, and the duration of diabetes was 21.6 ± 12.1 years at enrollment. The FinnDiane Study is a nationwide multicenter cohort study of genetic, clinical, and environmental risk factors for microvascular and macrovascular complications in type 1 diabetes. […] all type 1 diabetic patients in the FinnDiane database with follow-up data and without a history of stroke at baseline were included. […] Fifteen patients were confirmed to have an SAH, and thus the crude incidence of SAH was 40.9 (95% CI 22.9–67.4) per 100,000 person-years. Ten out of these 15 SAHs were nonaneurysmal SAHs […] The crude incidence of nonaneurysmal SAH was 27.3 (13.1–50.1) per 100,000 person-years. None of the 10 nonaneurysmal SAHs were fatal. […] Only 3 out of 10 patients did not have verified diabetic microvascular or macrovascular complications prior to the nonaneurysmal SAH event. […] Four patients with type 1 diabetes had a fatal SAH, and all these patients died within 24 h after SAH.”

The presented study results suggest that the incidence of nonaneurysmal SAH is high among patients with type 1 diabetes. […] It is of note that smoking type 1 diabetic patients had a significantly increased risk of nonaneurysmal and all-cause SAHs. Smoking also increases the risk of microvascular complications in insulin-treated diabetic patients, and these patients more often have retinal and renal microangiopathy than never-smokers (8). […] Given the high incidence of nonaneurysmal SAH in patients with type 1 diabetes and microvascular changes (i.e., diabetic retinopathy and nephropathy), the results support the hypothesis that nonaneurysmal SAH is a microvascular rather than macrovascular subtype of stroke.”

“Only one patient with type 1 diabetes had a confirmed aneurysmal SAH. Four other patients died suddenly due to an SAH. If these four patients with type 1 diabetes and a fatal SAH had an aneurysmal SAH, which, taking into account the autopsy reports and imaging findings, is very likely, aneurysmal SAH may be an exceptionally deadly event in type 1 diabetes. Population-based evidence suggests that up to 45% of people die during the first 30 days after SAH, and 18% die at emergency rooms or outside hospitals (9). […] Contrary to aneurysmal SAH, nonaneurysmal SAH is virtually always a nonfatal event (1014). This also supports the view that nonaneurysmal SAH is a disease of small intracranial vessels, i.e., a microvascular disease. Diabetic retinopathy, a chronic microvascular complication, has been associated with an increased risk of stroke in patients with diabetes (15,16). Embryonically, the retina is an outgrowth of the brain and is similar in its microvascular properties to the brain (17). Thus, it has been suggested that assessments of the retinal vasculature could be used to determine the risk of cerebrovascular diseases, such as stroke […] Most interestingly, the incidence of nonaneurysmal SAH was at least two times higher than the incidence of aneurysmal SAH in type 1 diabetic patients. In comparison, the incidence of nonaneurysmal SAH is >10 times lower than the incidence of aneurysmal SAH in the general adult population (21).”

vii. HbA1c and the Risks for All-Cause and Cardiovascular Mortality in the General Japanese Population.

Keep in mind when looking at these data that this is type 2 data. Type 1 diabetes is very rare in Japan and the rest of East Asia.

“The risk for cardiovascular death was evaluated in a large cohort of participants selected randomly from the overall Japanese population. A total of 7,120 participants (2,962 men and 4,158 women; mean age 52.3 years) free of previous CVD were followed for 15 years. Adjusted hazard ratios (HRs) and 95% CIs among categories of HbA1c (<5.0%, 5.0–5.4%, 5.5–5.9%, 6.0–6.4%, and ≥6.5%) for participants without treatment for diabetes and HRs for participants with diabetes were calculated using a Cox proportional hazards model.

RESULTS During the study, there were 1,104 deaths, including 304 from CVD, 61 from coronary heart disease, and 127 from stroke (78 from cerebral infarction, 25 from cerebral hemorrhage, and 24 from unclassified stroke). Relations to HbA1c with all-cause mortality and CVD death were graded and continuous, and multivariate-adjusted HRs for CVD death in participants with HbA1c 6.0–6.4% and ≥6.5% were 2.18 (95% CI 1.22–3.87) and 2.75 (1.43–5.28), respectively, compared with participants with HbA1c <5.0%. Similar associations were observed between HbA1c and death from coronary heart disease and death from cerebral infarction.

CONCLUSIONS High HbA1c levels were associated with increased risk for all-cause mortality and death from CVD, coronary heart disease, and cerebral infarction in general East Asian populations, as in Western populations.”

November 15, 2017 Posted by | Cardiology, Diabetes, Epidemiology, Medicine, Neurology, Pharmacology, Studies | Leave a comment

Organic Chemistry (II)

I have included some observations from the second half of the book below, as well as some links to topics covered.

“[E]nzymes are used routinely to catalyse reactions in the research laboratory, and for a variety of industrial processes involving pharmaceuticals, agrochemicals, and biofuels. In the past, enzymes had to be extracted from natural sources — a process that was both expensive and slow. But nowadays, genetic engineering can incorporate the gene for a key enzyme into the DNA of fast growing microbial cells, allowing the enzyme to be obtained more quickly and in far greater yield. Genetic engineering has also made it possible to modify the amino acids making up an enzyme. Such modified enzymes can prove more effective as catalysts, accept a wider range of substrates, and survive harsher reaction conditions. […] New enzymes are constantly being discovered in the natural world as well as in the laboratory. Fungi and bacteria are particularly rich in enzymes that allow them to degrade organic compounds. It is estimated that a typical bacterial cell contains about 3,000 enzymes, whereas a fungal cell contains 6,000. Considering the variety of bacterial and fungal species in existence, this represents a huge reservoir of new enzymes, and it is estimated that only 3 per cent of them have been investigated so far.”

“One of the most important applications of organic chemistry involves the design and synthesis of pharmaceutical agents — a topic that is defined as medicinal chemistry. […] In the 19th century, chemists isolated chemical components from known herbs and extracts. Their aim was to identify a single chemical that was responsible for the extract’s pharmacological effects — the active principle. […] It was not long before chemists synthesized analogues of active principles. Analogues are structures which have been modified slightly from the original active principle. Such modifications can often improve activity or reduce side effects. This led to the concept of the lead compound — a compound with a useful pharmacological activity that could act as the starting point for further research. […] The first half of the 20th century culminated in the discovery of effective antimicrobial agents. […] The 1960s can be viewed as the birth of rational drug design. During that period there were important advances in the design of effective anti-ulcer agents, anti-asthmatics, and beta-blockers for the treatment of high blood pressure. Much of this was based on trying to understand how drugs work at the molecular level and proposing theories about why some compounds were active and some were not.”

“[R]ational drug design was boosted enormously towards the end of the century by advances in both biology and chemistry. The sequencing of the human genome led to the identification of previously unknown proteins that could serve as potential drug targets. […] Advances in automated, small-scale testing procedures (high-throughput screening) also allowed the rapid testing of potential drugs. In chemistry, advances were made in X-ray crystallography and NMR spectroscopy, allowing scientists to study the structure of drugs and their mechanisms of action. Powerful molecular modelling software packages were developed that allowed researchers to study how a drug binds to a protein binding site. […] the development of automated synthetic methods has vastly increased the number of compounds that can be synthesized in a given time period. Companies can now produce thousands of compounds that can be stored and tested for pharmacological activity. Such stores have been called chemical libraries and are routinely tested to identify compounds capable of binding with a specific protein target. These advances have boosted medicinal chemistry research over the last twenty years in virtually every area of medicine.”

“Drugs interact with molecular targets in the body such as proteins and nucleic acids. However, the vast majority of clinically useful drugs interact with proteins, especially receptors, enzymes, and transport proteins […] Enzymes are […] important drug targets. Drugs that bind to the active site and prevent the enzyme acting as a catalyst are known as enzyme inhibitors. […] Enzymes are located inside cells, and so enzyme inhibitors have to cross cell membranes in order to reach them—an important consideration in drug design. […] Transport proteins are targets for a number of therapeutically important drugs. For example, a group of antidepressants known as selective serotonin reuptake inhibitors prevent serotonin being transported into neurons by transport proteins.”

“The main pharmacokinetic factors are absorption, distribution, metabolism, and excretion. Absorption relates to how much of an orally administered drug survives the digestive enzymes and crosses the gut wall to reach the bloodstream. Once there, the drug is carried to the liver where a certain percentage of it is metabolized by metabolic enzymes. This is known as the first-pass effect. The ‘survivors’ are then distributed round the body by the blood supply, but this is an uneven process. The tissues and organs with the richest supply of blood vessels receive the greatest proportion of the drug. Some drugs may get ‘trapped’ or sidetracked. For example fatty drugs tend to get absorbed in fat tissue and fail to reach their target. The kidneys are chiefly responsible for the excretion of drugs and their metabolites.”

“Having identified a lead compound, it is important to establish which features of the compound are important for activity. This, in turn, can give a better understanding of how the compound binds to its molecular target. Most drugs are significantly smaller than molecular targets such as proteins. This means that the drug binds to quite a small region of the protein — a region known as the binding site […]. Within this binding site, there are binding regions that can form different types of intermolecular interactions such as van der Waals interactions, hydrogen bonds, and ionic interactions. If a drug has functional groups and substituents capable of interacting with those binding regions, then binding can take place. A lead compound may have several groups that are capable of forming intermolecular interactions, but not all of them are necessarily needed. One way of identifying the important binding groups is to crystallize the target protein with the drug bound to the binding site. X-ray crystallography then produces a picture of the complex which allows identification of binding interactions. However, it is not always possible to crystallize target proteins and so a different approach is needed. This involves synthesizing analogues of the lead compound where groups are modified or removed. Comparing the activity of each analogue with the lead compound can then determine whether a particular group is important or not. This is known as an SAR study, where SAR stands for structure–activity relationships.” Once the important binding groups have been identified, the pharmacophore for the lead compound can be defined. This specifies the important binding groups and their relative position in the molecule.”

“One way of identifying the active conformation of a flexible lead compound is to synthesize rigid analogues where the binding groups are locked into defined positions. This is known as rigidification or conformational restriction. The pharmacophore will then be represented by the most active analogue. […] A large number of rotatable bonds is likely to have an adverse effect on drug activity. This is because a flexible molecule can adopt a large number of conformations, and only one of these shapes corresponds to the active conformation. […] In contrast, a totally rigid molecule containing the required pharmacophore will bind the first time it enters the binding site, resulting in greater activity. […] It is also important to optimize a drug’s pharmacokinetic properties such that it can reach its target in the body. Strategies include altering the drug’s hydrophilic/hydrophobic properties to improve absorption, and the addition of substituents that block metabolism at specific parts of the molecule. […] The drug candidate must [in general] have useful activity and selectivity, with minimal side effects. It must have good pharmacokinetic properties, lack toxicity, and preferably have no interactions with other drugs that might be taken by a patient. Finally, it is important that it can be synthesized as cheaply as possible”.

“Most drugs that have reached clinical trials for the treatment of Alzheimer’s disease have failed. Between 2002 and 2012, 244 novel compounds were tested in 414 clinical trials, but only one drug gained approval. This represents a failure rate of 99.6 per cent as against a failure rate of 81 per cent for anti-cancer drugs.”

“It takes about ten years and £160 million to develop a new pesticide […] The volume of global sales increased 47 per cent in the ten-year period between 2002 and 2012, while, in 2012, total sales amounted to £31 billion. […] In many respects, agrochemical research is similar to pharmaceutical research. The aim is to find pesticides that are toxic to ‘pests’, but relatively harmless to humans and beneficial life forms. The strategies used to achieve this goal are also similar. Selectivity can be achieved by designing agents that interact with molecular targets that are present in pests, but not other species. Another approach is to take advantage of any metabolic reactions that are unique to pests. An inactive prodrug could then be designed that is metabolized to a toxic compound in the pest, but remains harmless in other species. Finally, it might be possible to take advantage of pharmacokinetic differences between pests and other species, such that a pesticide reaches its target more easily in the pest. […] Insecticides are being developed that act on a range of different targets as a means of tackling resistance. If resistance should arise to an insecticide acting on one particular target, then one can switch to using an insecticide that acts on a different target. […] Several insecticides act as insect growth regulators (IGRs) and target the moulting process rather than the nervous system. In general, IGRs take longer to kill insects but are thought to cause less detrimental effects to beneficial insects. […] Herbicides control weeds that would otherwise compete with crops for water and soil nutrients. More is spent on herbicides than any other class of pesticide […] The synthetic agent 2,4-D […] was synthesized by ICI in 1940 as part of research carried out on biological weapons […] It was first used commercially in 1946 and proved highly successful in eradicating weeds in cereal grass crops such as wheat, maize, and rice. […] The compound […] is still the most widely used herbicide in the world.”

“The type of conjugated system present in a molecule determines the specific wavelength of light absorbed. In general, the more extended the conjugation, the higher the wavelength absorbed. For example, β-carotene […] is the molecule responsible for the orange colour of carrots. It has a conjugated system involving eleven double bonds, and absorbs light in the blue region of the spectrum. It appears red because the reflected light lacks the blue component. Zeaxanthin is very similar in structure to β-carotene, and is responsible for the yellow colour of corn. […] Lycopene absorbs blue-green light and is responsible for the red colour of tomatoes, rose hips, and berries. Chlorophyll absorbs red light and is coloured green. […] Scented molecules interact with olfactory receptors in the nose. […] there are around 400 different olfactory protein receptors in humans […] The natural aroma of a rose is due mainly to 2-phenylethanol, geraniol, and citronellol.”

“Over the last fifty years, synthetic materials have largely replaced natural materials such as wood, leather, wool, and cotton. Plastics and polymers are perhaps the most visible sign of how organic chemistry has changed society. […] It is estimated that production of global plastics was 288 million tons in 2012 […] Polymerization involves linking molecular strands called polymers […]. By varying the nature of the monomer, a huge range of different polymers can be synthesized with widely differing properties. The idea of linking small molecular building blocks into polymers is not a new one. Nature has been at it for millions of years using amino acid building blocks to make proteins, and nucleotide building blocks to make nucleic acids […] The raw materials for plastics come mainly from oil, which is a finite resource. Therefore, it makes sense to recycle or depolymerize plastics to recover that resource. Virtually all plastics can be recycled, but it is not necessarily economically feasible to do so. Traditional recycling of polyesters, polycarbonates, and polystyrene tends to produce inferior plastics that are suitable only for low-quality goods.”

Adipic acid.
Protease. Lipase. Amylase. Cellulase.
Conformational change.
Process chemistry (chemical development).
Clinical trial.
N-Methyl carbamate.
Colony collapse disorder.
Ecdysone receptor.
Quinone outside inhibitors (QoI).
11-cis retinal.
Synthetic dyes.
Methylene blue.
Artificial sweeteners.
Addition polymer.
Condensation polymer.
Polyvinyl chloride.
Bisphenol A.
Allotropes of carbon.
Carbon nanotube.
Molecular switch.

November 11, 2017 Posted by | Biology, Books, Botany, Chemistry, Medicine, Pharmacology, Zoology | Leave a comment


This book is almost exclusively devoted to covering biochemistry topics. When the coverage is decent I find biochemistry reasonably interesting – for example I really liked Beer, Björk & Beardall’s photosynthesis book – and the coverage here was okay, but not more than that. I think that Ball was trying to cover a bit too much ground, or perhaps that there was really too much ground to cover for it to even make sense to try to write a book on this particular topic in a series like this. I learned a lot though.

As usual I’ve added some quotes from the coverage below, as well as some additional links to topics/concepts/people/etc. covered in the book.

“Most atoms on their own are highly reactive – they have a predisposition to join up with other atoms. Molecules are collectives of atoms, firmly welded together into assemblies that may contain anything up to many millions of them. […] By molecules, we generally mean assemblies of a discrete, countable number of atoms. […] Some pure elements adopt molecular forms; others do not. As a rough rule of thumb, metals are non-molecular […] whereas non-metals are molecular. […] molecules are the smallest units of meaning in chemistry. It is through molecules, not atoms, that one can tell stories in the sub-microscopic world. They are the words; atoms are just the letters. […] most words are distinct aggregates of several letters arranged in a particular order. We often find that longer words convey subtler and more finely nuanced meanings. And in molecules, as in words, the order in which the component parts are put together matters: ‘save’ and ‘vase’ do not mean the same thing.”

“There are something like 60,000 different varieties of protein molecule in human cells, each conducting a highly specialized task. It would generally be impossible to guess what this task is merely by looking at a protein. They are undistinguished in appearance, mostly globular in shape […] and composed primarily of carbon, hydrogen, nitrogen, oxygen, and a little sulphur. […] There are twenty varieties of amino acids in natural proteins. In the chain, one amino acid is linked to the next via a covalent bond called a peptide bond. Both molecules shed a few extraneous atoms to make this linkage, and the remainder – another link in the chain – is called a residue. The chain itself is termed a polypeptide. Any string of amino acid residues is a polypeptide. […] In a protein the order of amino acids along the chain – the sequence – is not arbitrary. It is selected […] to ensure that the chain will collapse and curl up in water into the precisely determined globular form of the protein, with all parts of the chain in the right place. This shape can be destroyed by warming the protein, a process called denaturation. But many proteins will fold up again spontaneously into the same globular structure when cooled. In other words, the chain has a kind of memory of its folded shape. The details of this folding process are still not fully understood – it is, in fact, one of the central unsolved puzzles of molecular biology. […] proteins are made not in the [cell] nucleus but in a different compartment called the endoplasmic reticulum […]. The gene is transcribed first into a molecule related to DNA, called RNA (ribonucleic acid). The RNA molecules travel from the nucleus to the endoplasmic reticulum, where they are translated to proteins. The proteins are then shipped off to where they are needed.”

[M]icrofibrils aggregate together in various ways. For example, they can gather in a staggered arrangement to form thick strands called banded fibrils. […] Banded fibrils constitute the connective tissues between cells – they are the cables that hold our flesh together. Bone consists of collagen banded fibrils sprinkled with tiny crystals of the mineral hydroxyapatite, which is basically calcium phosphate. Because of the high protein content of bone, it is flexible and resilient as well as hard. […] In contrast to the disorderly tangle of connective tissue, the eye’s cornea contains collagen fibrils packed side by side in an orderly manner. These fibrils are too small to scatter light, and so the material is virtually transparent. The basic design principle – one that recurs often in nature – is that, by tinkering with the chemical composition and, most importantly, the hierarchical arrangement of the same basic molecules, it is possible to extract several different kinds of material properties. […] cross-links determine the strength of the material: hair and fingernail are more highly cross-linked than skin. Curly or frizzy hair can be straightened by breaking some of [the] sulphur cross-links to make the hairs more pliable. […] Many of the body’s structural fabrics are proteins. Unlike enzymes, structural proteins do not have to conduct any delicate chemistry, but must simply be (for instance) tough, or flexible, or waterproof. In principle many other materials besides proteins would suffice; and indeed, plants use cellulose (a sugar-based polymer) to make their tissues.”

“In many ways, it is metabolism and not replication that provides the best working definition of life. Evolutionary biologists would say that we exist in order to reproduce – but we are not, even the most amorous of us, trying to reproduce all the time. Yet, if we stop metabolizing, even for a minute or two, we are done for. […] Whether waking or asleep, our bodies stay close to a healthy temperature of 37 °C. There is only one way of doing this: our cells are constantly pumping out heat, a by-product of metabolism. Heat is not really the point here – it is simply unavoidable, because all conversion of energy from one form to another squanders some of it this way. Our metabolic processes are primarily about making molecules. Cells cannot survive without constantly reinventing themselves: making new amino acids for proteins, new lipids for membranes, new nucleic acids so that they can divide.”

“In the body, combustion takes place in a tightly controlled, graded sequence of steps, and some chemical energy is drawn off and stored at each stage. […] A power station burns coal, oil, or gas […]. Burning is just a means to an end. The heat is used to turn water into steam; the pressure of the steam drives turbines; the turbines spin and send wire coils whirling in the arms of great magnets, which induces an electrical current in the wire. Energy is passed on, from chemical to heat to mechanical to electrical. And every plant has a barrage of regulatory and safety mechanisms. There are manual checks on pressure gauges and on the structural integrity of moving parts. Automatic sensors make the measurements. Failsafe devices avert catastrophic failure. Energy generation in the cell is every bit as complicated. […] The cell seems to have thought of everything, and has protein devices for fine-tuning it all.”

ATP is the key to the maintenance of cellular integrity and organization, and so the cell puts a great deal of effort into making as much of it as possible from each molecule of glucose that it burns. About 40 per cent of the energy released by the combustion of food is conserved in ATP molecules. ATP is rich in energy because it is like a coiled spring. It contains three phosphate groups, linked like so many train carriages. Each of these phosphate groups has a negative charge; this means that they repel one another. But because they are joined by chemical bonds, they cannot escape one another […]. Straining to get away, the phosphates pull an energetically powerful punch. […] The links between phosphates can be snipped in a reaction that involves water […] called hydrolysis (‘splitting with water’). Each time a bond is hydrolysed, energy is released. Setting free the outermost phosphate converts ATP to adenosine diphosphate (ADP); cleave the second phosphate and it becomes adenosine monophosphate (AMP). Both severances release comparable amounts of energy.”

“Burning sugar is a two-stage process, beginning with its transformation to a molecule called pyruvate in a process known as glycolysis […]. This involves a sequence of ten enzyme-catalysed steps. The first five of these split glucose in half […], powered by the consumption of ATP molecules: two of them are ‘decharged’ to ADP for every glucose molecule split. But the conversion of the fragments to pyruvate […] permits ATP to be recouped from ADP. Four ATP molecules are made this way, so that there is an overall gain of two ATP molecules per glucose molecule consumed. Thus glycolysis charges the cell’s batteries. Pyruvate then normally enters the second stage of the combustion process: the citric acid cycle, which requires oxygen. But if oxygen is scarce – that is, under anaerobic conditions – a contingency plan is enacted whereby pyruvate is instead converted to the molecule lactate. […] The first thing a mitochondrion does is convert pyruvate enzymatically to a molecule called acetyl coenzyme A (CoA). The breakdown of fatty acids and glycerides from fats also eventually generates acetyl CoA. The [citric acid] cycle is a sequence of eight enzyme-catalysed reactions that transform acetyl CoA first to citric acid and then to various other molecules, ending with […] oxaloacetate. This end is a new beginning, for oxaloacetate reacts with acetyl CoA to make citric acid. In some of the steps of the cycle, carbon dioxide is generated as a by-product. It dissolves in the bloodstream and is carried off to the lungs to be exhaled. Thus in effect the carbon in the original glucose molecules is syphoned off into the end product carbon dioxide, completing the combustion process. […] Also syphoned off from the cycle are electrons – crudely speaking, the citric acid cycle sends an electrical current to a different part of the mitochondrion. These electrons are used to convert oxygen molecules and positively charged hydrogen ions to water – an energy-releasing process. The energy is captured and used to make ATP in abundance.”

“While mammalian cells have fuel-burning factories in the form of mitochondria, the solar-power centres in the cells of plant leaves are compartments called chloroplasts […] chloroplast takes carbon dioxide and water, and from them constructs […] sugar. […] In the first part of photosynthesis, light is used to convert NADP to an electron carrier (NADPH) and to transform ADP to ATP. This is effectively a charging-up process that primes the chloroplast for glucose synthesis. In the second part, ATP and NADPH are used to turn carbon dioxide into sugar, in a cyclic sequence of steps called the Calvin–Benson cycle […] There are several similarities between the processes of aerobic metabolism and photosynthesis. Both consist of two distinct sub-processes with separate evolutionary origins: a linear sequence of reactions coupled to a cyclic sequence that regenerates the molecules they both need. The bridge between glycolysis and the citric acid cycle is the electron-ferrying NAD molecule; the two sub-processes of photosynthesis are bridged by the cycling of an almost identical molecule, NAD phosphate (NADP).”

“Despite the variety of messages that hormones convey, the mechanism by which the signal is passed from a receptor protein at the cell surface to the cell’s interior is the same in almost all cases. It involves a sequence of molecular interactions in which molecules transform one another down a relay chain. In cell biology this is called signal transduction. At the same time as relaying the message, these interactions amplify the signal so that the docking of a single hormone molecule to a receptor creates a big response inside the cell. […] The receptor proteins span the entire width of the membrane; the hormone-binding site protrudes on the outer surface, while the base of the receptor emerges from the inner surface […]. When the receptor binds its target hormone, a shape change is transmitted to the lower face of the protein, which enables it to act as an enzyme. […] The participants of all these processes [G protein, guanosine diphosphate and -triphosphate, adenylate cyclase… – figured it didn’t matter if I left out a few details – US…] are stuck to the cell wall. But cAMP floats freely in the cell’s cytoplasm, and is able to carry the signal into the cell interior. It is called a ‘second messenger’, since it is the agent that relays the signal of the ‘first messenger’ (the hormone) into the community of the cell. Cyclic AMP becomes attached to protein molecules called protein kinases, whereupon they in turn become activated as enzymes. Most protein kinases switch other enzymes on and off by attaching phosphate groups to them – a reaction called phosphorylation. […] The process might sound rather complicated, but it is really nothing more than a molecular relay. The signal is passed from the hormone to its receptor, then to the G protein, on to an enzyme and thence to the second messenger, and further on to a protein kinase, and so forth. The G-protein mechanism of signal transduction was discovered in the 1970s by Alfred Gilman and Martin Rodbell, for which they received the 1994 Nobel Prize for medicine. It represents one of the most widespread means of getting a message across a cell membrane. […] it is not just hormonal signalling that makes use of the G-protein mechanism. Our senses of vision and smell, which also involve the transmission of signals, employ the same switching process.”

“Although axon signals are electrical, they differ from those in the metal wires of electronic circuitry. The axon is basically a tubular cell membrane decorated along its length with channels that let sodium and potassium ions in and out. Some of these ion channels are permanently open; others are ‘gated’, opening or closing in response to electrical signals. And some are not really channels at all but pumps, which actively transport sodium ions out of the cell and potassium ions in. These sodium-potassium pumps can move ions […] powered by ATP. […] Drugs that relieve pain typically engage with inhibitory receptors. Morphine, the main active ingredient of opium, binds to so-called opioid receptors in the spinal cord, which inhibit the transmission of pain signals to the brain. There are also opioid receptors in the brain itself, which is why morphine and related opiate drugs have a mental as well as a somatic effect. These receptors in the brain are the binding sites of peptide molecules called endorphins, which the brain produces in response to pain. Some of these are themselves extremely powerful painkillers. […] Not all pain-relieving drugs (analgesics) work by blocking the pain signal. Some prevent the signal from ever being sent. Pain signals are initiated by peptides called prostaglandins, which are manufactured and released by distressed cells. Aspirin (acetylsalicylic acid) latches onto and inhibits one of the enzymes responsible for prostaglandin synthesis, cutting off the cry of pain at its source. Unfortunately, prostaglandins are also responsible for making the mucus that protects the stomach lining […], so one of the side effects of aspirin is the risk of ulcer formation.”

“Shape changes […] are common when a receptor binds its target. If binding alone is the objective, a big shape change is not terribly desirable, since the internal rearrangements of the receptor make heavy weather of the binding event and may make it harder to achieve. This is why many supramolecular hosts are designed so that they are ‘pre-organized’ to receive their guests, minimizing the shape change caused by binding.”

“The way that a protein chain folds up is determined by its amino-acid sequence […] so the ‘information’ for making a protein is uniquely specified by this sequence. DNA encodes this information using […] groups of three bases [to] represent each amino acid. This is the genetic code.* How a particular protein sequence determines the way its chain folds is not yet fully understood. […] Nevertheless, the principle of information flow in the cell is clear. DNA is a manual of information about proteins. We can think of each chromosome as a separate chapter, each gene as a word in that chapter (they are very long words!), and each sequential group of three bases in the gene as a character in the word. Proteins are translations of the words into another language, whose characters are amino acids. In general, only when the genetic language is translated can we understand what it means.”

“It is thought that only about 2–3 per cent of the entire human genome codes for proteins. […] Some people object to genetic engineering on the grounds that it is ethically wrong to tamper with the fundamental material of life – DNA – whether it is in bacteria, humans, tomatoes, or sheep. One can understand such objections, and it would be arrogant to dismiss them as unscientific. Nevertheless, they do sit uneasily with what we now know about the molecular basis of life. The idea that our genetic make-up is sacrosanct looks hard to sustain once we appreciate how contingent, not to say arbitrary, that make-up is. Our genomes are mostly parasite-riddled junk, full of the detritus of over three billion years of evolution.”


Roald Hoffmann.
Molecular solid.
Covalent bond.
Visible spectrum.
X-ray crystallography.
Electron microscope.
Valence (chemistry).
John Dalton.
Organic chemistry.
Synthetic dye industry/Alizarin.
Paul Ehrlich (staining).
Retrosynthetic analysis. [I would have added a link to ‘rational synthesis as well here if there’d been a good article on that topic, but I wasn’t able to find one. Anyway: “Organic chemists call [the] kind of procedure […] in which a starting molecule is converted systematically, bit by bit, to the desired product […] a rational synthesis.”]
Paclitaxel synthesis.
Tryptophan synthase.
Amino acid.
Protein folding.
Peptide bond.
Hydrogen bond.
Structural gene. Regulatory gene.
Gregor Mendel.
Mitochondrial DNA.
RNA world.
Artificial gene synthesis.
Carbon nanotube.
Cytochrome c oxidase.
ATP synthase.
Thylakoid membrane.
Motor protein. Dynein. Kinesin.
Sliding filament theory of muscle action.
Supramolecular chemistry.
Hormone. Endocrine system.
Intron. Exon.
Molecular electronics.

October 30, 2017 Posted by | Biology, Books, Botany, Chemistry, Genetics, Neurology, Pharmacology | Leave a comment

A few diabetes papers of interest

i. The Pharmacogenetics of Type 2 Diabetes: A Systematic Review.

“We performed a systematic review to identify which genetic variants predict response to diabetes medications.

RESEARCH DESIGN AND METHODS We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation.

RESULTS Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). […] Significant medication–gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis.

CONCLUSIONS We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics.”

“In this systematic review, we identified 34 articles on the pharmacogenetics of diabetes medications, with several reporting statistically significant interactions between genetic variants and medications for glycemic outcomes. Most pharmacogenetic interactions were only evaluated in a single study, did not use a control group, and/or did not report enough information to judge internal validity. However, our results do suggest specific, biologically plausible, gene–medication interactions, and we recommend confirmation of the biologically plausible interactions as a priority, including those for drug transporters, metabolizers, and targets of action. […] Given the number of comparisons reported in the included studies and the lack of accounting for multiple comparisons in approximately 53% of studies, many of the reported findings may [however] be false positives.”

ii. Insights Offered by Economic Analyses.

“This issue of Diabetes Care includes three economic analyses. The first describes the incremental costs of diabetes over a lifetime and highlights how interventions to prevent diabetes may reduce lifetime costs (1). The second demonstrates that although an expensive, intensive lifestyle intervention for type 2 diabetes does not reduce adverse cardiovascular outcomes over 10 years, it significantly reduces the costs of non-intervention−related medical care (2). The third demonstrates that although the use of the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria for the screening and diagnosis of gestational diabetes mellitus (GDM) results in a threefold increase in the number of people labeled as having GDM, it reduces the risk of maternal and neonatal adverse health outcomes and reduces costs (3). The first report highlights the enormous potential value of intervening in adults at high risk for type 2 diabetes to prevent its development. The second illustrates the importance of measuring economic outcomes in addition to standard clinical outcomes to fully assess the value of new treatments. The third demonstrates the importance of rigorously weighing the costs of screening and treatment against the costs of health outcomes when evaluating new approaches to care.”

“The costs of diabetes monitoring and treatment accrue as of function of the duration of diabetes, so adults who are younger at diagnosis are more likely to survive to develop the late, expensive complications of diabetes, thus they incur higher lifetime costs attributable to diabetes. Zhuo et al. report that people with diabetes diagnosed at age 40 spend approximately $125,000 more for medical care over their lifetimes than people without diabetes. For people diagnosed with diabetes at age 50, the discounted lifetime excess medical spending is approximately $91,000; for those diagnosed at age 60, it is approximately $54,000; and for those diagnosed at age 65, it is approximately $36,000 (1).

These results are very consistent with results reported by the Diabetes Prevention Program (DPP) Research Group, which assessed the cost-effectiveness of diabetes prevention. […] In the simulated lifetime economic analysis [included in that study] the lifestyle intervention was more cost-effective in younger participants than in older participants (5). By delaying the onset of type 2 diabetes, the lifestyle intervention delayed or prevented the need for diabetes monitoring and treatment, surveillance of diabetic microvascular and neuropathic complications, and treatment of the late, expensive complications and comorbidities of diabetes, including end-stage renal disease and cardiovascular disease (5). Although this finding was controversial at the end of the randomized, controlled clinical trial, all but 1 of 12 economic analyses published by 10 research groups in nine countries have demonstrated that lifestyle intervention for the prevention of type 2 diabetes is very cost-effective, if not cost-saving, compared with a placebo intervention (6).

Empiric, within-trial economic analyses of the DPP have now demonstrated that the incremental costs of the lifestyle intervention are almost entirely offset by reductions in the costs of medical care outside the study, especially the cost of self-monitoring supplies, prescription medications, and outpatient and inpatient care (7). Over 10 years, the DPP intensive lifestyle intervention cost only ∼$13,000 per quality-adjusted life-year gained when the analysis used an intent-to-treat approach (7) and was even more cost-effective when the analysis assessed outcomes and costs among adherent participants (8).”

“The American Diabetes Association has reported that although institutional care (hospital, nursing home, and hospice care) still account for 52% of annual per capita health care expenditures for people with diabetes, outpatient medications and supplies now account for 30% of expenditures (9). Between 2007 and 2012, annual per capita expenditures for inpatient care increased by 2%, while expenditures for medications and supplies increased by 51% (9). As the costs of diabetes medications and supplies continue to increase, it will be even more important to consider cost savings arising from the less frequent use of medications when evaluating the benefits of nonpharmacologic interventions.”

iii. The Lifetime Cost of Diabetes and Its Implications for Diabetes Prevention. (This is the Zhuo et al. paper mentioned above.)

“We aggregated annual medical expenditures from the age of diabetes diagnosis to death to determine lifetime medical expenditure. Annual medical expenditures were estimated by sex, age at diagnosis, and diabetes duration using data from 2006–2009 Medical Expenditure Panel Surveys, which were linked to data from 2005–2008 National Health Interview Surveys. We combined survival data from published studies with the estimated annual expenditures to calculate lifetime spending. We then compared lifetime spending for people with diabetes with that for those without diabetes. Future spending was discounted at 3% annually. […] The discounted excess lifetime medical spending for people with diabetes was $124,600 ($211,400 if not discounted), $91,200 ($135,600), $53,800 ($70,200), and $35,900 ($43,900) when diagnosed with diabetes at ages 40, 50, 60, and 65 years, respectively. Younger age at diagnosis and female sex were associated with higher levels of lifetime excess medical spending attributed to diabetes.

CONCLUSIONS Having diabetes is associated with substantially higher lifetime medical expenditures despite being associated with reduced life expectancy. If prevention costs can be kept sufficiently low, diabetes prevention may lead to a reduction in long-term medical costs.”

The selection criteria employed in this paper are not perfect; they excluded all individuals below the age of 30 “because they likely had type 1 diabetes”, which although true is only ‘mostly true’. Some of those individuals had(/have) type 2, but if you’re evaluating prevention schemes it probably makes sense to error on the side of caution (better to miss some type 2 patients than to include some type 1s), assuming the timing of the intervention is not too important. This gets more complicated if prevention schemes are more likely to have large and persistent effects in young people – however I don’t think that’s the case, as a counterpoint drug adherence studies often seem to find that young people aren’t particularly motivated to adhere to their treatment schedules compared to their older counterparts (who might have more advanced disease and so are more likely to achieve symptomatic relief by adhering to treatments).

A few more observations from the paper:

“The prevalence of participants with diabetes in the study population was 7.4%, of whom 54% were diagnosed between the ages of 45 and 64 years. The mean age at diagnosis was 55 years, and the mean length of time since diagnosis was 9.4 years (39% of participants with diabetes had been diagnosed for ≤5 years, 32% for 6–15 years, and 27% for ≥16 years). […] The observed annual medical spending for people with diabetes was $13,966—more than twice that for people without diabetes.”

“Regardless of diabetes status, the survival-adjusted annual medical spending decreased after age 60 years, primarily because of a decreasing probability of survival. Because the probability of survival decreased more rapidly in people with diabetes than in those without, corresponding spending declined as people died and no longer accrued medical costs. For example, among men diagnosed with diabetes at age 40 years, 34% were expected to survive to age 80 years; among men of the same age who never developed diabetes, 55% were expected to survive to age 80 years. The expected annual expenditure for a person diagnosed with diabetes at age 40 years declined from $8,500 per year at age 40 years to $3,400 at age 80 years, whereas the expenses for a comparable person without diabetes declined from $3,900 to $3,200 over that same interval. […] People diagnosed with diabetes at age 40 years lived with the disease for an average of 34 years after diagnosis. Those diagnosed when older lived fewer years and, therefore, lost fewer years of life. […] The annual excess medical spending attributed to diabetes […] was smaller among people who were diagnosed at older ages. For men diagnosed at age 40 years, annual medical spending was $3,700 higher than that of similar men without diabetes; spending was $2,900 higher for those diagnosed at age 50 years; $2,200 higher for those diagnosed at age 60 years; and $2,000 higher for those diagnosed at age 65 years. Among women diagnosed with diabetes, the excess annual medical spending was consistently higher than for men of the same age at diagnosis.”

“Regardless of age at diagnosis, people with diabetes spent considerably more on health care after age 65 years than their nondiabetic counterparts. Health care spending attributed to diabetes after age 65 years ranged from $23,900 to $40,900, depending on sex and age at diagnosis. […] Of the total excess lifetime medical spending among an average diabetic patient diagnosed at age 50 years, prescription medications and inpatient care accounted for 44% and 35% of costs, respectively. Outpatient care and other medical care accounted for 17% and 4% of costs, respectively.”

“Our findings differed from those of studies of the lifetime costs of other chronic conditions. For instance, smokers have a lower average lifetime medical cost than nonsmokers (29) because of their shorter life spans. Smokers have a life expectancy about 10 years less than those who do not smoke (30); life expectancy is 16 years less for those who develop smoking-induced cancers (31). As a result, smoking cessation leads to increased lifetime spending (32). Studies of the lifetime costs for an obese person relative to a person with normal body weight show mixed results: estimated excess lifetime medical costs for people with obesity range from $3,790 less to $39,000 more than costs for those who are nonobese (33,34). […] obesity, when considered alone, results in much lower annual excess medical costs than diabetes (–$940 to $1,150 for obesity vs. $2,000 to $4,700 for diabetes) when compared with costs for people who are nonobese (33,34).”

iv. Severe Hypoglycemia and Mortality After Cardiovascular Events for Type 1 Diabetic Patients in Sweden.

“This study examines factors associated with all-cause mortality after cardiovascular complications (myocardial infarction [MI] and stroke) in patients with type 1 diabetes. In particular, we aim to determine whether a previous history of severe hypoglycemia is associated with increased mortality after a cardiovascular event in type 1 diabetic patients.

Hypoglycemia is the most common and dangerous acute complication of type 1 diabetes and can be life threatening if not promptly treated (1). The average individual with type 1 diabetes experiences about two episodes of symptomatic hypoglycemia per week, with an annual prevalence of 30–40% for hypoglycemic episodes requiring assistance for recovery (2). We define severe hypoglycemia to be an episode of hypoglycemia that requires hospitalization in this study. […] Patients with type 1 diabetes are more susceptible to hypoglycemia than those with type 2 diabetes, and therefore it is potentially of greater relevance if severe hypoglycemia is associated with mortality (6).”

“This study uses a large linked data set comprising health records from the Swedish National Diabetes Register (NDR), which were linked to administrative records on hospitalization, prescriptions, and national death records. […] [The] study is based on data from four sources: 1) risk factor data from the Swedish NDR […], 2) hospital records of inpatient episodes from the National Inpatients Register (IPR) […], 3) death records […], and 4) prescription data records […]. A study comparing registered diagnoses in the IPR with information in medical records found positive predictive values of IPR diagnoses were 85–95% for most diagnoses (8). In terms of NDR coverage, a recent study found that 91% of those aged 18–34 years and with type 1 diabetes in the Prescribed Drug Register could be matched with those in the NDR for 2007–2009 (9).”

“The outcome of the study was all-cause mortality after a major cardiovascular complication (MI or stroke). Our sample for analysis included patients with type 1 diabetes who visited a clinic after 2002 and experienced a major cardiovascular complication after this clinic visit. […] We define type 1 diabetes as diabetes diagnosed under the age of 30 years, being reported as being treated with insulin only at some clinic visit, and when alive, having had at least one prescription for insulin filled per year between 2006 and 2010 […], and not having filled a prescription for metformin at any point between July 2005 and December 2010 (under the assumption that metformin users were more likely to be type 2 diabetes patients).”

“Explanatory variables included in both models were type of complication (MI or stroke), age at complication, duration of diabetes, sex, smoking status, HbA1c, BMI, systolic blood pressure, diastolic blood pressure, chronic kidney disease status based on estimated glomerular filtration rate, microalbuminuria and macroalbuminuria status, HDL, LDL, total–to–HDL cholesterol ratio, triglycerides, lipid medication status, clinic visits within the year prior to the CVD event, and prior hospitalization events: hypoglycemia, hyperglycemia, MI, stroke, heart failure, AF, amputation, PVD, ESRD, IHD/unstable angina, PCI, and CABG. The last known value for each clinical risk factor, prior to the cardiovascular complication, was used for analysis. […] Initially, all explanatory variables were included and excluded if the variable was not statistically significant at a 5% level (P < 0.05) via stepwise backward elimination.” [Aaaaaaargh! – US. These guys are doing a lot of things right, but this is not one of them. Just to mention this one more time: “Generally, hypothesis testing is a very poor basis for model selection […] There is no statistical theory that supports the notion that hypothesis testing with a fixed α level is a basis for model selection.” (Burnham & Anderson)]

“Patients who had prior hypoglycemic events had an estimated HR for mortality of 1.79 (95% CI 1.37–2.35) in the first 28 days after a CVD event and an estimated HR of 1.25 (95% CI 1.02–1.53) of mortality after 28 days post CVD event in the backward regression model. The univariate analysis showed a similar result compared with the backward regression model, with prior hypoglycemic events having an estimated HR for mortality of 1.79 (95% CI 1.38–2.32) and 1.35 (95% CI 1.11–1.65) in the logistic and Cox regressions, respectively. Even when all explanatory factors were included in the models […], the mortality increase associated with a prior severe hypoglycemic event was still significant, and the P values and SE are similar when compared with the backward stepwise regression. Similarly, when explanatory factors were included individually, the mortality increase associated with a prior severe hypoglycemic event was also still significant.” [Again, this sort of testing scheme is probably not a good approach to getting at a good explanatory model, but it’s what they did – US]

“The 5-year cumulative estimated mortality risk for those without complications after MI and stroke were 40.1% (95% CI 35.2–45.1) and 30.4% (95% CI 26.3–34.6), respectively. Patients with prior heart failure were at the highest estimated 5-year cumulative mortality risk, with those who suffered an MI and stroke having a 56.0% (95% CI 47.5–64.5) and 44.0% (95% CI 35.8–52.2) 5-year cumulative mortality risk, respectively. Patients who had a prior severe hypoglycemic event and suffered an MI had an estimated 5-year cumulative mortality risk at age 60 years of 52.4% (95% CI 45.3–59.5), and those who suffered a stroke had a 5-year cumulative mortality risk of 39.8% (95% CI 33.4–46.3). Patients at age 60 years who suffer a major CVD complication have over twofold risk of 5-year mortality compared with the general type 1 diabetic Swedish population, who had an estimated 5-year mortality risk of 13.8% (95% CI 12.0–16.1).”

“We found evidence that prior severe hypoglycemia is associated with reduced survival after a major CVD event but no evidence that prior severe hypoglycemia is associated with an increased risk of a subsequent CVD event.

Compared with the general type 1 diabetic Swedish population, a major CVD complication increased 5-year mortality risk at age 60 years by >25% and 15% in patients with an MI and stroke, respectively. Patients with a history of a hypoglycemic event had an even higher mortality after a major CVD event, with approximately an additional 10% being dead at the 5-year mark. This risk was comparable with that in those with late-stage kidney disease. This information is useful in determining the prognosis of patients after a major cardiovascular event and highlights the need to include this as a risk factor in simulation models (18) that are used to improve decision making (19).”

“This is the first study that has found some evidence of a dose-response relationship, where patients who experienced two or more severe hypoglycemic events had higher mortality after a cardiovascular event compared with those who experienced one severe hypoglycemic event. A lack of statistical power prevented us from investigating this further when we tried to stratify by number of prior severe hypoglycemic events in our regression models. There was no evidence of a dose-response relationship between repeated episodes of severe hypoglycemia and vascular outcomes or death in previous type 2 diabetes studies (5).”

v. Alterations in White Matter Structure in Young Children With Type 1 Diabetes.

“Careful regulation of insulin dosing, dietary intake, and activity levels are essential for optimal glycemic control in individuals with type 1 diabetes. However, even with optimal treatment many children with type 1 diabetes have blood glucose levels in the hyperglycemic range for more than half the day and in the hypoglycemic range for an hour or more each day (1). Brain cells may be especially sensitive to aberrant blood glucose levels, as glucose is the brain’s principal substrate for its energy needs.

Research in animal models has shown that white matter (WM) may be especially sensitive to dysglycemia-associated insult in diabetes (24). […] Early childhood is a period of rapid myelination and brain development (6) and of increased sensitivity to insults affecting the brain (6,7). Hence, study of the developing brain is particularly important in type 1 diabetes.”

“WM structure can be measured with diffusion tensor imaging (DTI), a method based on magnetic resonance imaging (MRI) that uses the movement of water molecules to characterize WM brain structure (8,9). Results are commonly reported in terms of mathematical scalars (representing vectors in vector space) such as fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD). FA reflects the degree of diffusion anisotropy of water (how diffusion varies along the three axes) within a voxel (three-dimensional pixel) and is determined by fiber diameter and density, myelination, and intravoxel fiber-tract coherence (increases in which would increase FA), as well as extracellular diffusion and interaxonal spacing (increases in which would decrease FA) (10). AD, a measure of water diffusivity along the main axis of diffusion within a voxel, is thought to reflect fiber coherence and structure of axonal membranes (increases in which would increase AD), as well as microtubules, neurofilaments, and axonal branching (increases in which would decrease AD) (11,12). RD, the mean of the diffusivities perpendicular to the vector with the largest eigenvalue, is thought to represent degree of myelination (13,14) (more myelin would decrease RD values) and axonal “leakiness” (which would increase RD). Often, however, a combination of these WM characteristics results in opposing contributions to the final observed FA/AD/RD value, and thus DTI scalars should not be interpreted globally as “good” or “bad” (15). Rather, these scalars can show between-group differences and relationships between WM structure and clinical variables and are suggestive of underlying histology. Definitive conclusions about histology of WM can only be derived from direct microscopic examination of biological tissue.”

“Children (ages 4 to <10 years) with type 1 diabetes (n = 127) and age-matched nondiabetic control subjects (n = 67) had diffusion weighted magnetic resonance imaging scans in this multisite neuroimaging study. Participants with type 1 diabetes were assessed for HbA1c history and lifetime adverse events, and glucose levels were monitored using a continuous glucose monitor (CGM) device and standardized measures of cognition.

RESULTS Between-group analysis showed that children with type 1 diabetes had significantly reduced axial diffusivity (AD) in widespread brain regions compared with control subjects. Within the type 1 diabetes group, earlier onset of diabetes was associated with increased radial diffusivity (RD) and longer duration was associated with reduced AD, reduced RD, and increased fractional anisotropy (FA). In addition, HbA1c values were significantly negatively associated with FA values and were positively associated with RD values in widespread brain regions. Significant associations of AD, RD, and FA were found for CGM measures of hyperglycemia and glucose variability but not for hypoglycemia. Finally, we observed a significant association between WM structure and cognitive ability in children with type 1 diabetes but not in control subjects. […] These results suggest vulnerability of the developing brain in young children to effects of type 1 diabetes associated with chronic hyperglycemia and glucose variability.”

“The profile of reduced overall AD in type 1 diabetes observed here suggests possible axonal damage associated with diabetes (30). Reduced AD was associated with duration of type 1 diabetes suggesting that longer exposure to diabetes worsens the insult to WM structure. However, measures of hyperglycemia and glucose variability were either not associated or were positively associated with AD values, suggesting that these measures did not contribute to the observed decreased AD in the type 1 diabetes group. A possible explanation for these observations is that several biological processes influence WM structure in type 1 diabetes. Some processes may be related to insulin insufficiency or C-peptide levels independent of glucose levels (31,32) and may affect WM coherence (and reduce AD values as observed in the between-group results). Other processes related to hyperglycemia and glucose variability may target myelin (resulting in reduced FA and increased RD) as well as reduced axonal branching (both would result in increased AD values). Alternatively, these seemingly conflicting AD observations may be due to a dominant effect of age, which could overshadow effects from dysglycemia.

Early age of onset is one of the most replicable risk factors for cognitive impairments in type 1 diabetes (33,34). It has been hypothesized that young children are especially vulnerable to brain insults resulting from episodes of chronic hyperglycemia, hypoglycemia, and acute hypoglycemic complications of type 1 diabetes (seizures and severe hypoglycemic episodes). In addition, fear of hypoglycemia often results in caregivers maintaining relatively higher blood glucose to avoid lows altogether (1), especially in very young children. However, our study suggests that this approach of aggressive hypoglycemia avoidance resulting in hyperglycemia may not be optimal and may be detrimental to WM structure in young children.

Neuronal damage (reflected in altered WM structure) may affect neuronal signal transfer and, thus, cognition (35). Cognitive domains commonly reported to be affected in children with type 1 diabetes include general intellectual ability, visuospatial abilities, attention, memory, processing speed, and executive function (3638). In our sample, even though the duration of illness was relatively short (2.9 years on average), there were modest but significant cognitive differences between children with type 1 diabetes and control subjects (24).”

“In summary, we present results from the largest study to date investigating WM structure in very young children with type 1 diabetes. We observed significant and widespread brain differences in the WM microstructure of children with type 1 diabetes compared with nondiabetic control subjects and significant associations between WM structure and measures of hyperglycemia, glucose variability, and cognitive ability in the type 1 diabetic population.”

vi. Ultrasound Findings After Surgical Decompression of the Tarsal Tunnel in Patients With Painful Diabetic Polyneuropathy: A Prospective Randomized Study.

“Polyneuropathy is a common complication in diabetes. The prevalence of neuropathy in patients with diabetes is ∼30%. During the course of the disease, up to 50% of the patients will eventually develop neuropathy (1). Its clinical features are characterized by numbness, tingling, or burning sensations and typically extend in a distinct stocking and glove pattern. Prevention plays a key role since poor glucose control is a major risk factor in the development of diabetic polyneuropathy (DPN) (1,2).

There is no clear definition for the onset of painful diabetic neuropathy. Different hypotheses have been formulated.

Hyperglycemia in diabetes can lead to osmotic swelling of the nerves, related to increased glucose conversion into sorbitol by the enzyme aldose reductase (2,3). High sorbitol concentrations might also directly cause axonal degeneration and demyelination (2). Furthermore, stiffening and thickening of ligamental structures and the plantar fascia make underlying structures more prone to biomechanical compression (46). A thicker and stiffer retinaculum might restrict movements and lead to alterations of the nerve in the tarsal tunnel.

Both swelling of the nerve and changes in the tarsal tunnel might lead to nerve damage through compression.

Furthermore, vascular changes may diminish endoneural blood flow and oxygen distribution. Decreased blood supply in the (compressed) nerve might lead to ischemic damage as well as impaired nerve regeneration.

Several studies suggest that surgical decompression of nerves at narrow anatomic sites, e.g., the tarsal tunnel, is beneficial and has a positive effect on pain, sensitivity, balance, long-term risk of ulcers and amputations, and quality of life (3,710). Since the effect of decompression of the tibial nerve in patients with DPN has not been proven with a randomized clinical trial, its contribution as treatment for patients with painful DPN is still controversial. […] In this study, we compare the mean CSA and any changes in shape of the tibial nerve before and after decompression of the tarsal tunnel using ultrasound in order to test the hypothesis that the tarsal tunnel leads to compression of the tibial nerve in patients with DPN.”

“This study, with a large sample size and standardized sonographic imaging procedure with a good reliability, is the first randomized controlled trial that evaluates the effect of decompression of the tibial nerve on the CSA. Although no effect on CSA after surgery was found, this study using ultrasound demonstrates a larger and swollen tibial nerve and thicker flexor retinaculum at the ankle in patients with DPN compared with healthy control subjects.”

I would have been interested to know if there were any observable changes in symptom relief measures post-surgery, even if such variables are less ‘objective’ than measures like CSA (less objective, but perhaps more relevant to the patient…), but the authors did not look at those kinds of variables.

vii. Nonalcoholic Fatty Liver Disease Is Independently Associated With an Increased Incidence of Chronic Kidney Disease in Patients With Type 1 Diabetes.

“Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions worldwide (1). Up to 30% of adults in the U.S. and Europe have NAFLD, and the prevalence of this disease is much higher in people with diabetes (1,2). Indeed, the prevalence of NAFLD on ultrasonography ranges from ∼50 to 70% in patients with type 2 diabetes (35) and ∼40 to 50% in patients with type 1 diabetes (6,7). Notably, patients with diabetes and NAFLD are also more likely to develop more advanced forms of NAFLD that may result in end-stage liver disease (8). However, accumulating evidence indicates that NAFLD is associated not only with liver-related morbidity and mortality but also with an increased risk of developing cardiovascular disease (CVD) and other serious extrahepatic complications (810).”

“Increasing evidence indicates that NAFLD is strongly associated with an increased risk of CKD [chronic kidney disease, US] in people with and without diabetes (11). Indeed, we have previously shown that NAFLD is associated with an increased prevalence of CKD in patients with both type 1 and type 2 diabetes (1517), and that NAFLD independently predicts the development of incident CKD in patients with type 2 diabetes (18). However, many of the risk factors for CKD are different in patients with type 1 and type 2 diabetes, and to date, it is uncertain whether NAFLD is an independent risk factor for incident CKD in type 1 diabetes or whether measurement of NAFLD improves risk prediction for CKD, taking account of traditional risk factors for CKD.

Therefore, the aim of the current study was to investigate 1) whether NAFLD is associated with an increased incidence of CKD and 2) whether measurement of NAFLD improves risk prediction for CKD, adjusting for traditional risk factors, in type 1 diabetic patients.”

“Using a retrospective, longitudinal cohort study design, we have initially identified from our electronic database all Caucasian type 1 diabetic outpatients with preserved kidney function (i.e., estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2) and with no macroalbuminuria (n = 563), who regularly attended our adult diabetes clinic between 1999 and 2001. Type 1 diabetes was diagnosed by the typical presentation of disease, the absolute dependence on insulin treatment for survival, the presence of undetectable fasting C-peptide concentrations, and the presence of anti–islet cell autoantibodies. […] Overall, 261 type 1 diabetic outpatients were included in the final analysis and were tested for the development of incident CKD during the follow-up period […] All participants were periodically seen (every 3–6 months) for routine medical examinations of glycemic control and chronic complications of diabetes. No participants were lost to follow-up. […] For this study, the development of incident CKD was defined as occurrence of eGFR <60 mL/min/1.73 m2 and/or macroalbuminuria (21). Both of these outcome measures were confirmed in all participants in a least two consecutive occasions (within 3–6 months after the first examination).”

“At baseline, the mean eGFRMDRD was 92 ± 23 mL/min/1.73 m2 (median 87.9 [IQR 74–104]), or eGFREPI was 98.6 ± 19 mL/min/1.73 m2 (median 99.7 [84–112]). Most patients (n = 234; 89.7%) had normal albuminuria, whereas 27 patients (10.3%) had microalbuminuria. NAFLD was present in 131 patients (50.2%). […] At baseline, patients who developed CKD at follow-up were older, more likely to be female and obese, and had a longer duration of diabetes than those who did not. These patients also had higher values of systolic blood pressure, A1C, triglycerides, serum GGT, and urinary ACR and lower values of eGFRMDRD and eGFREPI. Moreover, there was a higher percentage of patients with hypertension, metabolic syndrome, microalbuminuria, and some degree of diabetic retinopathy in patients who developed CKD at follow-up compared with those remaining free from CKD. The proportion using antihypertensive drugs (that always included the use of ACE inhibitors or angiotensin receptor blockers) was higher in those who progressed to CKD. Notably, […] this patient group also had a substantially higher frequency of NAFLD on ultrasonography.”

“During follow-up (mean duration 5.2 ± 1.7 years, range 2–10), 61 patients developed CKD using the MDRD study equation to estimate eGFR (i.e., ∼4.5% of participants progressed every year to eGFR <60 mL/min/1.73 m2 or macroalbuminuria). Of these, 28 developed an eGFRMDRD <60 mL/min/1.73 m2 with abnormal albuminuria (micro- or macroalbuminuria), 21 developed a reduced eGFRMDRD with normal albuminuria (but 9 of them had some degree of diabetic retinopathy at baseline), and 12 developed macroalbuminuria alone. None of them developed kidney failure requiring chronic dialysis. […] The annual eGFRMDRD decline for the whole cohort was 2.68 ± 3.5 mL/min/1.73 m2 per year. […] NAFLD patients had a greater annual decline in eGFRMDRD than those without NAFLD at baseline (3.28 ± 3.8 vs. 2.10 ± 3.0 mL/min/1.73 m2 per year, P < 0.005). Similarly, the frequency of a renal functional decline (arbitrarily defined as ≥25% loss of baseline eGFRMDRD) was greater among those with NAFLD than among those without the disease (26 vs. 11%, P = 0.005). […] Interestingly, BMI was not significantly associated with CKD.”

“Our novel findings indicate that NAFLD is strongly associated with an increased incidence of CKD during a mean follow-up of 5 years and that measurement of NAFLD improves risk prediction for CKD, independently of traditional risk factors (age, sex, diabetes duration, A1C, hypertension, baseline eGFR, and microalbuminuria [i.e., the last two factors being the strongest known risk factors for CKD]), in type 1 diabetic adults. Additionally, although NAFLD was strongly associated with obesity, obesity (or increased BMI) did not explain the association between NAFLD and CKD. […] The annual cumulative incidence rate of CKD in our cohort of patients (i.e., ∼4.5% per year) was essentially comparable to that previously described in other European populations with type 1 diabetes and similar baseline characteristics (∼2.5–9% of patients who progressed every year to CKD) (25,26). In line with previously published information (2528), we also found that hypertension, microalbuminuria, and lower eGFR at baseline were strong predictors of incident CKD in type 1 diabetic patients.”

“There is a pressing and unmet need to determine whether NAFLD is associated with a higher risk of CKD in people with type 1 diabetes. It has only recently been recognized that NAFLD represents an important burden of disease for type 2 diabetic patients (11,17,18), but the magnitude of the problem of NAFLD and its association with risk of CKD in type 1 diabetes is presently poorly recognized. Although there is clear evidence that NAFLD is closely associated with a higher prevalence of CKD both in those without diabetes (11) and in those with type 1 and type 2 diabetes (1517), only four prospective studies have examined the association between NAFLD and risk of incident CKD (18,2931), and only one of these studies was published in patients with type 2 diabetes (18). […] The underlying mechanisms responsible for the observed association between NAFLD and CKD are not well understood. […] The possible clinical implication for these findings is that type 1 diabetic patients with NAFLD may benefit from more intensive surveillance or early treatment interventions to decrease the risk for CKD. Currently, there is no approved treatment for NAFLD. However, NAFLD and CKD share numerous cardiometabolic risk factors, and treatment strategies for NAFLD and CKD should be similar and aimed primarily at modifying the associated cardiometabolic risk factors.”


October 25, 2017 Posted by | Cardiology, Diabetes, Epidemiology, Genetics, Health Economics, Medicine, Nephrology, Neurology, Pharmacology, Statistics, Studies | Leave a comment

A few diabetes papers of interest

i. Burden of Diabetic Foot Ulcers for Medicare and Private Insurers.

Some observations from the paper (my bold):

According to the American Diabetes Association, the annual cost of diabetes, which affects 22.3 million people in the U.S., was $245 billion in 2012: $176 billion in excess health care expenditures and $69 billion in reduced workforce productivity (1). While much of the excess health care cost is attributable to treatment of diabetes itself, a substantial amount of the cost differential arises via treatment of chronic complications such as those related to the heart, kidneys, and nervous system (1).

One common complication of diabetes is the development of foot ulcers. Historically, foot ulcers have been estimated to affect 1–4% of patients with diabetes annually (2,3) and as many as 25% of the patients with diabetes over their lifetimes (2). More recently, Margolis et al. (3) have estimated that the annual incidence of foot ulcers among patients with diabetes may be as high as 6%. Treatment of diabetic foot ulcers (DFUs) includes conventional wound management (e.g., debridement, moist dressings, and offloading areas of high pressure or friction) as well as more sophisticated treatments such as bioengineered cellular technologies and hyperbaric oxygen therapy (HBO) (4).

DFUs often require extensive healing time and are associated with increased risk for infections and other sequelae that can result in severe and costly outcomes (4). […] DFU patients have a low survival prognosis, with a 3-year cumulative mortality rate of 28% (6) and rates among amputated patients approaching 50% (7).”

“While DFU patients can require substantial amounts of resource use, little is known about the burden of DFUs imposed on the U.S. health care system and payers. In fact, we are aware of only two studies to date that have estimated the incremental medical resource use and costs of DFU beyond that of diabetes alone (6,8). Neither of these analyses, however, accounted for the many underlying differences between DFU and non-DFU patient populations, such as disproportionate presence of costly underlying comorbid conditions among DFU patients […] Other existing literature on the burden of DFUs in the U.S. calculated the overall health care costs (as opposed to incremental) without reference to a non-DFU control population (911). As a result of the variety of data and methodologies used, it is not surprising that the burden of DFUs reported in the literature is wide-ranging, with the average per-patient costs, for example, ranging from $4,595 per episode (9) to over $35,000 annually for all services (6).

The objective of this study was to expand and improve on previous research to provide a more robust, current estimate of incremental clinical and economic burden of DFUs. To do so, this analysis examined the differences in medical resource use and costs between patients with DFUs during a recent time period (January 2007–September 2011) and a matched control population with diabetes but without DFUs, using administrative claims records from nationally representative databases for Medicare and privately insured populations. […] [Our] criteria resulted in a final analytic sample of 231,438 Medicare patients, with 29,681 (12.8%) identified as DFU patients and the remaining 201,757 comprising the potential control population of non-DFU diabetic patients. For private insurance, 119,018 patients met the sample selection criteria, with 5,681 (4.8%) DFU patients and 113,337 potential controls (Fig. 1).”

Prior to matching, DFU patients were statistically different from the non-DFU control population on nearly every dimension examined during the 12-month preindex period. […] The matching process resulted in the identification of 27,878 pairs of DFU and control patients for Medicare and 4,536 pairs for private insurance that were very similar with regards to preindex patient characteristics […] [I]mportantly, the matched DFU and control groups had comparable health care costs during the 12 months prior to the index date (Medicare, $17,744 DFU and controls; private insurance, $14,761 DFU vs. $14,766 controls). […] Despite having matched the groups to ensure similar patient characteristics, DFU patients used significantly (P < 0.0001) more medical resources during the 12-month follow-up period than did the matched controls […]. Among matched Medicare patients, DFU patients had 138.2% more days hospitalized, 85.4% more days of home health care, 40.6% more ED visits, and 35.1% more outpatient/physician office visits. The results were similar for the privately insured DFU patients, who had 173.5% more days hospitalized, 230.0% more days of home health care, 109.0% more ED visits, and 42.5% more outpatient/physician office visits than matched controls. […] The rate of lower limb amputations was 3.8% among matched Medicare DFU patients and 5.0% among matched privately insured DFU patients. In contrast, observed lower limb amputation rates among diabetic patients without foot ulcer were only 0.04% in Medicare and 0.02% in private insurance.”

Increased medical resource utilization resulted in DFU patients having approximately twice the costs as the matched non-DFU controls […], with annual incremental per-patient medical costs ranging from $11,710 for Medicare ($28,031 vs. $16,320; P < 0.0001) to $15,890 for private insurance ($26,881 vs. $10,991; P < 0.0001). All places of service (i.e., inpatient, ED, outpatient/physician office, home health care, and other) contributed approximately equally to the cost differential among Medicare patients. For the privately insured, however, increased inpatient costs ($17,061 vs. $6,501; P < 0.0001) were responsible for nearly two-thirds of the overall cost differential, […] resulting in total incremental direct health care (i.e., medical + prescription drug) costs of $16,883 ($31,419 vs. $14,536; P < 0.0001). Substantial proportions of the incremental medical costs were attributable to claims with DFU-related diagnoses or procedures for both Medicare (45.1%) and privately insured samples (60.3%).”

“Of the 4,536 matched pairs of privately insured patients, work-loss information was available for 575 DFU patients and 857 controls. DFU patients had $3,259 in excess work-loss costs ($6,311 vs. $3,052; P < 0.0001) compared with matched controls, with disability and absenteeism comprising $1,670 and $1,589 of the overall differential, respectively […] The results indicate that compared with diabetic patients without foot ulcers, DFU patients miss more days of work due to medical-related absenteeism and to disability, imposing additional burden on employers.”

“These estimates indicate that DFU imposes substantial burden on payers beyond that required to treat diabetes itself. For example, prior research has estimated annual per-patient incremental health care expenditures for patients with diabetes (versus those without diabetes) of approximately $7,900 (1). The estimates of this analysis suggest that the presence of DFU further compounds these incremental treatment costs by adding $11,710 to $16,883 per patient. Stated differently, the results indicate that the excess health care costs of DFU are approximately twice that attributable to treatment of diabetes itself, and that the presence of DFU approximately triples the excess cost differential versus a population of patients without diabetes.

“Using estimates of the total U.S. diabetes population (22.3 million) (1) and the midpoint (3.5%) of annual DFU incidence estimates (1–6%) (2,3), the results of this analysis suggest an annual incremental payer burden of DFU ranging from $9.1 billion (22.3 million patients with diabetes × 3.5% DFU incidence × $11,710 Medicare cost differential) to $13.2 billion (22.3 million patients with diabetes × 3.5% DFU incidence × $16,883 private insurance cost differential). These estimates, moreover, likely understate the actual burden of DFU because the incremental costs referenced in this calculation do not include excess work-loss costs described above, prescription drug costs for Medicare patients, out-of-pocket costs paid by the patient, costs borne by supplemental insurers, and other (non-work loss) indirect costs such as those associated with premature mortality, reduced quality of life, and informal caregiving.”

ii. Contributors to Mortality in High-Risk Diabetic Patients in the Diabetes Heart Study.

“Rates of cardiovascular disease (CVD) are two- to fourfold greater in individuals with type 2 diabetes compared with nondiabetic individuals, and up to 65% of all-cause mortality among individuals with type 2 diabetes is attributed to CVD (1,2). However, the risk profile is not uniform for all individuals affected by diabetes (35). Coronary artery calcified plaque (CAC), determined using computed tomography, is a measure of CVD burden (6,7). CAC scores have been shown to be an independent predictor of CVD outcomes and mortality in population-based studies (810) and a powerful predictor of all-cause and CVD mortality in individuals affected by type 2 diabetes (4,1115).

In the Diabetes Heart Study (DHS), individuals with CAC >1,000 were found to have greater than 6-fold (16) and 11-fold (17) increased risk for all-cause mortality and CVD mortality, respectively, after 7 years of follow-up. With this high risk for adverse outcomes, it is noteworthy that >50% of the DHS sample with CAC >1,000 have lived with this CVD burden for (now) an average of over 12 years. This suggests that outcomes vary in the type 2 diabetic patient population, even among individuals with the highest risk. This study examined the subset of DHS participants with CAC >1,000 and evaluated whether differences in a range of clinical factors and measurements, including modifiable CVD risk factors, provided further insights into risk for mortality.”

“This investigation focused on 371 high-risk participants (from 260 families) […] The goal of this analysis was to identify clinical and other characteristics that influence risk for all-cause mortality in high-risk (baseline CAC >1,000) DHS participants. […] a predominance of traditional CVD risk factors, including older age, male sex, elevated BMI, and high rates of dyslipidemia and hypertension, was evident in this high-risk subgroup (Table 1). These participants were followed for 8.2 ± 3.0 years (mean ± SD), over which time 41% died. […] a number of indices continued to significantly predict outcome following adjustment for other CVD risk factors (including age, sex, and medication use) […]. Higher cholesterol and LDL concentrations were associated with an increased risk (∼1.3-fold) for mortality […] Slightly larger increases in risk for mortality were observed with changes in kidney function (1.3- to 1.4-fold) and elevated CRP (∼1.4-fold) […] use of cholesterol-lowering medication was less common among the deceased participants; those reporting no use of cholesterol-lowering medication at baseline were at a 1.4-fold increased risk of mortality […] these results confirm that, even among this high-risk group, heterogeneity in known CVD risk factors and associations with adverse outcomes are still observed and support their ongoing consideration as useful tools for individual risk assessment. Finally, the data presented here suggest that use of cholesterol-lowering medication was strongly associated with protection, supporting the known beneficial effects of cholesterol management on CVD risk (28,29). […] data suggest that cholesterol-lowering medications may be used less than recommended and need to be more aggressively targeted as a critical modifiable risk factor.”

iii. Neurological Consequences of Diabetic Ketoacidosis at Initial Presentation of Type 1 Diabetes in a Prospective Cohort Study of Children.

“Patients aged 6–18 years with and without DKA at diagnosis were studied at four time points: <48 h, 5 days, 28 days, and 6 months postdiagnosis. Patients underwent magnetic resonance imaging (MRI) and spectroscopy with cognitive assessment at each time point. Relationships between clinical characteristics at presentation and MRI and neurologic outcomes were examined using multiple linear regression, repeated-measures, and ANCOVA analyses.”

“With DKA, cerebral white matter showed the greatest alterations with increased total white matter volume and higher mean diffusivity in the frontal, temporal, and parietal white matter. Total white matter volume decreased over the first 6 months. For gray matter in DKA patients, total volume was lower at baseline and increased over 6 months. […] Of note, although changes in total and regional brain volumes over the first 5 days resolved, they were associated with poorer delayed memory recall and poorer sustained and divided attention at 6 months. Age at time of presentation and pH level were predictors of neuroimaging and functional outcomes.

CONCLUSIONS DKA at type 1 diabetes diagnosis results in morphologic and functional brain changes. These changes are associated with adverse neurocognitive outcomes in the medium term.”

“This study highlights the common nature of transient focal cerebral edema and associated impaired mental state at presentation with new-onset type 1 diabetes in children. We demonstrate that alterations occur most markedly in cerebral white matter, particularly in the frontal lobes, and are most prominent in the youngest children with the most dramatic acidemia. […] early brain changes were associated with persisting alterations in attention and memory 6 months later. Children with DKA did not differ in age, sex, SES, premorbid need for school assistance/remediation, or postdiagnosis clinical trajectory. Earlier diagnosis of type 1 diabetes in children may avoid the complication of DKA and the neurological consequences documented in this study and is worthy of a major public health initiative.”

“In relation to clinical risk factors, the degree of acidosis and younger age appeared to be the greatest risk factors for alterations in cerebral structure. […] cerebral volume changes in the frontal, temporal, and parietal regions in the first week after diagnosis were associated with lower attention and memory scores 6 months later, suggesting that functional information processing difficulties persist after resolution of tissue water increases in cerebral white matter. These findings have not been reported to date but are consistent with the growing concern over academic performance in children with diabetes (2). […] Brain injury should no longer be considered a rare complication of DKA. This study has shown that it is both frequent and persistent.” (my bold)

iv. Antihypertensive Treatment and Resistant Hypertension in Patients With Type 1 Diabetes by Stages of Diabetic Nephropathy.

“High blood pressure (BP) is a risk factor for coronary artery disease, heart failure, and stroke, as well as for chronic kidney disease. Furthermore, hypertension has been estimated to affect ∼30% of patients with type 1 diabetes (1,2) and both parallels and precedes the worsening of kidney disease in these patients (35). […] Despite strong evidence that intensive treatment of elevated BP reduces the risk of cardiovascular disease and microvascular complications, as well as improves the prognosis of patients with diabetic nephropathy (especially with the use of ACE inhibitors [ACEIs] and angiotensin II antagonists [angiotensin receptor blockers, ARBs]) (1,911), treatment targets and recommendations seem difficult to meet in clinical practice (1215). This suggests that the patients might either show poor adherence to the treatment and lifestyle changes or have a suboptimal drug regimen. It is evident that most patients with hypertension might require multiple-drug therapy to reach treatment goals (16). However, certain subgroups of the patients have been considered to have resistant hypertension (RH). RH is defined as office BP that remains above target even after using a minimum of three antihypertensive drugs at maximal tolerated doses, from different classes, one of which is a diuretic. Also, patients with controlled BP using four or more antihypertensive drugs are considered resistant to treatment (17).”

“The true prevalence of RH is unknown, but clinical trials suggest a share between 10 and 30% of the hypertensive patients in the general population (18). […] Only a few studies have considered BP control and treatment in patients with type 1 diabetes (2,15,22). Typically these studies have been limited to a small number of participants, which has not allowed stratifying of the patients according to the nephropathy status. The rate of RH is therefore unknown in patients with type 1 diabetes in general and with respect to different stages of diabetic nephropathy. Therefore, we estimated to what extent patients with type 1 diabetes meet the BP targets proposed by the ADA guidelines. We also evaluated the use of antihypertensive medication and the prevalence of RH in the patients stratified by stage of diabetic nephropathy.”

“[A]ll adult patients with type 1 diabetes from >80 hospitals and primary healthcare centers across Finland were asked to participate. Type 1 diabetes was defined by age at onset of diabetes <40 years, C-peptide ≤0.3 nmol/L, and insulin treatment initiated within 1 year of diagnosis, if C-peptide was not measured. […] we used two different ADA BP targets: <130/85 mmHg, which was the target until 2000 (6), and <130/80 mmHg, which was the target between 2001 and 2012 (7). Patients were divided into groups based on whether their BP had reached the target or not and whether the antihypertensive drug was in use or not. […] uncontrolled hypertension was defined as failure to achieve target BP, based on these two different ADA guidelines, despite use of antihypertensive medication. RH was defined as failure to achieve the goal BP (<130/85 mmHg) even after using a minimum of three antihypertensive drugs, from different classes, one of which was a diuretic. […] On the basis of eGFR (mL/min/1.73 m2) level, patients were classified into five groups according to the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines: stage 1 eGFR ≥90, stage 2 eGFR 60–89, stage 3 eGFR 30–59, stage 4 eGFR 15–29, and stage 5 eGFR <15. Patients who were on dialysis were classified into stage 5. […] A total of 3,678 patients with complete data on systolic and diastolic BP and nephropathy status were identified from the FinnDiane database. […] The mean age was 38.0 ± 12.0 and mean duration of diabetes 22.1 ± 12.3 years.  […] The patients with advanced diabetic nephropathy had higher BP, worse dyslipidemia, poorer glycemic control, and more insulin resistance and macrovascular complications. BMI values were lower in the dialysis patients, probably due to renal cachexia.”

“Of all patients, 60.9% did not reach the BP target <130/85 mmHg, and the proportion was 70.3% with the target of <130/80 mmHg. […] The patients who were not on target had higher age and longer duration of diabetes and were more likely to be men. They also had poorer glycemic and lipid control as well as more micro- and macrovascular complications. […] Based on the BP target <130/85 mmHg, more than half of the patients in the normoalbuminuria group did not reach the BP target, and the share increased along with the worsening of nephropathy; two-thirds of the patients in the microalbuminuria group and fourfifths in the macroalbuminuria group were not on target, while even 90% of the dialysis and kidney transplant patients did not reach the target (Fig. 1A). Based on the stricter BP target of <130/80 mmHg, the numbers were obviously worse, but the trend was the same (Fig. 1B).”

“About 37% of the FinnDiane patients had antihypertensive treatment […] Whereas 14.1% of the patients with normal AER [Albumin Excretion Rate] had antihypertensive treatment, the proportions were 60.5% in the microalbuminuric, 90.3% in the macroalbuminuric, 88.6% in the dialysis, and 91.2% in the kidney transplant patients. However, in all groups, only a minority of the patients had BP values on target with the antihypertensive drug treatment they were prescribed […] The mean numbers of antihypertensive drugs varied within the nephropathy groups between those who had BP on target and those who did not […]. However, only in the micro- (P = 0.02) and macroalbuminuria (P = 0.003) groups were the mean numbers of the drugs higher if the BP was not on target, compared with those who had reached the targets. Notably, among the patients with normoalbuminuria who had not reached the BP target, 58% and, of the patients with microalbuminuria, 61% were taking only one antihypertensive drug. In contrast, more than half of the dialysis and 40% of the macroalbuminuric and transplanted patients, who had not reached the targets, had at least three drugs in their regimen. Moreover, one-fifth of the dialysis, 15% of the macroalbuminuric, and 10% of the transplanted patients had at least four antihypertensive drugs in use without reaching the target (Table 2). Almost all patients treated with antihypertensive drugs in the normo-, micro-, and macroalbuminuria groups (76% of normo-, 93% of micro-, and 89% of macrolbuminuric patients) had ACEIs or ARBs in the regimen. The proportions were lower in the ESRD groups: 42% of the dialysis and 29% of the transplanted patients were taking these drugs.”

“In general, the prevalence of RH was 7.9% for all patients with type 1 diabetes (n = 3,678) and 21.2% for the antihypertensive drug–treated patients (n = 1,370). The proportion was higher in men than in women (10.0 vs. 5.7%, P < 0.0001) […] When the patients were stratified by nephropathy status, the figures changed; in the normoalbuminuria group, the prevalence of RH was 1.2% of all and 8.7% of the drug treated patients. The corresponding numbers were 4.7 and 7.8% for the microalbuminuric patients, 28.1 and 31.2% for the macroalbuminuric patients, 36.6 and 41.3% for the patients on dialysis, and 26.3 and 28.8% for the kidney-transplanted patients, respectively […] The prevalence of RH also increased along with the worsening of renal function. The share was 1.4% for all and 7.4% for drug-treated patients at KDOQI stage 1. The corresponding numbers were 3.8 and 10.0% for the patients at stage 2, 26.6 and 30.0% for the patients at stage 3, 54.8 and 56.0% for the patients at stage 4, and 48.0 and 52.1% for those at stage 5, when kidney transplantation patients were excluded. […] In a multivariate logistic regression analysis, higher age, lower eGFR, higher waist-to-hip ratio, higher triglycerides, as well as microalbuminuria and macroalbuminuria, when normoalbuminuria was the reference category, were independently associated with RH […] A separate analysis also showed that dietary sodium intake, based on urinary sodium excretion rate, was independently associated with RH.”

“The current study shows that the prevalence of RH in patients with type 1 diabetes increases alongside the worsening of diabetic nephropathy. Whereas less than one-tenth of the antihypertensive drug–treated patients with normo- or microalbuminuria met the criteria for RH, the proportions were substantially higher among the patients with overt nephropathy: one-third of the patients with macroalbuminuria or a transplanted kidney and even 40% of the patients on dialysis. […] the prevalence of RH for the drug-treated patients was even higher (56%) in patients at the predialysis stage (eGFR 15–29). The findings are consistent with other studies that have demonstrated that chronic kidney disease is a strong predictor of failure to achieve BP targets despite the use of three or more different types of antihypertensive drugs in the general hypertensive population (26).”

“The prevalence of RH was 21.2% of the patients treated with antihypertensive drugs. Previous studies have indicated a prevalence of RH of 13% among patients being treated for hypertension (1921,27). […] the prevalence [of RH] seems to be […] higher among the drug-treated type 1 diabetic patients. These figures can only partly be explained by the use of a lower treatment target for BP, as recommended for patients with diabetes (6), since even when we used the BP target recommended for hypertensive patients (<140/90 mmHg), our data still showed a higher prevalence of RH (17%).”

“The study also confirmed previous findings that a large number of patients with type 1 diabetes do not achieve the recommended BP targets. Although the prevalence of RH increased with the severity of diabetic nephropathy, our data also suggest that patients with normo- and microalbuminuria might have a suboptimal drug regimen, since the majority of those who had not reached the BP target were taking only one antihypertensive drug. […] There is therefore an urgent need to improve antihypertensive treatment, not only in patients with overt nephropathy but also in those who have elevated BP without complications or early signs of renal disease. Moreover, further emphasis should be placed on the transplanted patients, since it is well known that hypertension affects both graft and patient survival negatively (30).” (my bold)

v. Association of Autoimmunity to Autonomic Nervous Structures With Nerve Function in Patients With Type 1 Diabetes: A 16-Year Prospective Study.

“Neuropathy is a chronic complication that includes a number of distinct syndromes and autonomic dysfunctions and contributes to increase morbidity and mortality in the diabetic population. In particular, cardiovascular autonomic neuropathy (CAN) is an independent risk factor for mortality in type 1 diabetes and is associated with poor prognosis and poor quality of life (13). Cardiovascular (CV) autonomic regulation rests upon a balance between sympathetic and parasympathetic innervation of the heart and blood vessels controlling heart rate and vascular dynamics. CAN encompasses several clinical manifestations, from resting tachycardia to fatal arrhythmia and silent myocardial infarction (4).

The mechanisms responsible for altered neural function in diabetes are not fully understood, and it is assumed that multiple mutually perpetuating pathogenic mechanisms may concur. These include dysmetabolic injury, neurovascular insufficiency, deficiency of neurotrophic growth factors and essential fatty acids, advanced glycosylation products (5,6), and autoimmune damage. Independent cross-sectional and prospective (713) studies identified circulating autoantibodies to autonomic nervous structures and hypothesized that immune determinants may be involved in autonomic nerve damage in type 1 diabetes. […] However, demonstration of a cause–effect relationship between antibodies (Ab) and diabetic autonomic neuropathy awaits confirmation.”

“We report on a 16-year follow-up study specifically designed to prospectively examine a cohort of patients with type 1 diabetes and aimed at assessing whether the presence of circulating Ab to autonomic nervous structures is associated with increased risk and predictive value of developing CAN. This, in turn, would be highly suggestive of the involvement of autoimmune mechanisms in the pathogenesis of this complication.”

“The present prospective study, conducted in young patients without established autonomic neuropathy at recruitment and followed for over 16 years until adulthood, strongly indicates that a cause–effect relationship may exist between auto-Ab to autonomic nervous tissues and development of diabetic autonomic neuropathy. Incipient or established CAN (22) reached a prevalence of 68% among the Ab-positive patients, significantly higher compared with the Ab-negative patients. […] Logistic regression analysis indicates that auto-Ab carry an almost 15-fold increased RR of developing an abnormal DB [deep breathing] test over 16 years and an almost sixfold increase of developing at least one abnormal CV [cardiovascular] test, independent of other variables. […] Circulating Ab to autonomic structures are associated with the development of autonomic dysfunction in young diabetic patients independent of glycemic control. […] autoimmune mechanisms targeting sympathetic and parasympathetic structures may play a primary etiologic role in the development and progression of autonomic dysfunction in type 1 diabetes in the long term. […] positivity for auto-Ab had a high positive predictive value for the later development of autonomic neuropathy.”

“Diabetic autonomic neuropathy, possibly the least recognized and most overlooked of diabetes complications, has increasingly gained attention as an independent predictor of silent myocardial ischemia and mortality, as consistently indicated by several cross-sectional studies (2,3,33). The pooled prevalence rate risk for silent ischemia is estimated at 1.96 by meta-analysis studies (5). In this report, established CAN (22) was detected in nearly 20% of young adult patients with acceptable metabolic control, after over approximately 23 years of diabetes duration, against 12% of patients of the same cohort with subtle asymptomatic autonomic dysfunction (one abnormal CV test) a decade earlier, in line with other studies in type 1 diabetes (2,24). Approximately 30% of the patients developed signs of peripheral somatic neuropathy not associated with autonomic dysfunction. This discrepancy suggests the participation of pathogenic mechanisms different from metabolic control and a distinct clinical course, as indicated by the DCCT study, where hyperglycemia had a less robust relationship with autonomic than somatic neuropathy (6).”

“Furthermore, this study shows that autonomic neuropathy, together with female sex and the occurrence of severe hypoglycemia, is a major determinant for poor quality of life in patients with type 1 diabetes. This is in agreement with previous reports (35) and linked to such invalidating symptoms as orthostatic hypotension and chronic diarrhea. […] In conclusion, the current study provides persuasive evidence for a primary pathogenic role of autoimmunity in the development of autonomic diabetic neuropathy. However, the mechanisms through which auto-Ab impair their target organ function, whether through classical complement action, proapoptotic effects of complement, enhanced antigen presentation, or channelopathy (26,39,40), remain to be elucidated.” (my bold)

vi. Body Composition Is the Main Determinant for the Difference in Type 2 Diabetes Pathophysiology Between Japanese and Caucasians.

“According to current understanding, the pathophysiology of type 2 diabetes is different in Japanese compared with Caucasians in the sense that Japanese are unable to compensate insulin resistance with increased insulin secretion to the same extent as Caucasians. Prediabetes and early stage diabetes in Japanese are characterized by reduced β-cell function combined with lower degree of insulin resistance compared with Caucasians (810). In a prospective, cross-sectional study of individuals with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT), it was demonstrated that Japanese in Japan were more insulin sensitive than Mexican Americans in the U.S. and Arabs in Israel (11). The three populations also differed with regards to β-cell response, whereas the disposition index — a measure of insulin secretion relative to insulin resistance — was similar across ethnicities for NGT and IGT participants. These studies suggest that profound differences in type 2 diabetes pathophysiology exist between different populations. However, few attempts have been made to establish the underlying demographic or lifestyle-related factors such as body composition, physical fitness, and physical activity leading to these differences.”

“The current study aimed at comparing Japanese and Caucasians at various glucose tolerance states, with respect to 1) insulin sensitivity and β-cell response and 2) the role of demographic, genetic, and lifestyle-related factors as underlying predictors for possible ethnic differences in insulin sensitivity and β-cell response. […] In our study, glucose profiles from OGTTs [oral glucose tolerance tests] were similar in Japanese and Caucasians, whereas insulin and C-peptide responses were lower in Japanese participants compared with Caucasians. In line with these observations, measures of β-cell response were generally lower in Japanese, who simultaneously had higher insulin sensitivity. Moreover, β-cell response relative to the degree of insulin resistance as measured by disposition indices was virtually identical in the two populations. […] We […] confirmed the existence of differences in insulin sensitivity and β-cell response between Japanese and Caucasians and showed for the first time that a major part of these differences can be explained by differences in body composition […]. On the basis of these results, we propose a similar pathophysiology of type 2 diabetes in Caucasians and Japanese with respect to insulin sensitivity and β-cell function.”

October 12, 2017 Posted by | Cardiology, Diabetes, Epidemiology, Health Economics, Medicine, Nephrology, Neurology, Pharmacology, Studies | Leave a comment

Diabetes and the Brain (V)

I have blogged this book in some detail in the past, but I never really finished my intended coverage of the book. This post is an attempt to rectify this.

Below I have added some quotes and observations from some of the chapters I have not covered in my previous posts about the book. I bolded some key observations along the way.

A substantial number of studies have assessed the effect of type 2 diabetes on cognitive functioning with psychometric tests. The majority of these studies reported subtle decrements in individuals with type 2 diabetes relative to non-diabetic controls (2, 4). […] the majority of studies in patients with type 2 diabetes reported moderate reductions in neuropsychological test performance, mainly in memory, information-processing speed, and mental flexibility, a pattern that is also observed in aging-related cognitive decline. […] the observed cognitive decrements are relatively subtle and rather non-specific. […] All in all, disturbances in glucose and insulin metabolism and associated vascular risk factors are associated with modest reductions in cognitive performance in “pre-diabetic stages.” Consequently, it may well be that the cognitive decrements that can be observed in patients with type 2 diabetes also start to develop before the actual onset of the diabetes. […] Because the different vascular and metabolic risk factors that are clustered in the metabolic syndrome are strongly interrelated, the contribution of each of the individual factor will be difficult to assess.” 

“Aging-related changes on brain imaging include vascular lesions and focal and global atrophy. Vascular lesions include (silent) brain infarcts and white-matter hyperintensities (WMHs). WMHs are common in the general population and their prevalence increases with age, approaching 100% by the age of 85 (69). The prevalence of lacunar infarcts also increases with age, up to 5% for symptomatic infarcts and 30% for silent infarcts by the age of 80 (70). In normal aging, the brain gradually reduces in size, which becomes particularly evident after the age of 70 (71). This loss of brain volume is global […] age-related changes of the brain […] are often relatively more pronounced in older patients with type 2 […] A recent systematic review showed that patients with diabetes have a 2-fold increased risk of (silent) infarcts compared to non-diabetic persons (75). The relationship between type 2 diabetes and WMHs is subject to debate. […] there are now clear indications that diabetes is a risk factor for WMH progression (82). […] The presence of the APOE ε4 allele is a risk factor for the development of Alzheimer’s disease (99). Patients with type 2 diabetes who carry the APOE ε4 allele appeared to have a 2-fold increased risk of dementia compared to persons with either of these risk factors in isolation (100, 101).”

In adults with type 1 diabetes the occurrence of microvascular complications is associated with reduced cognitive performance (137) and accelerated cognitive decline (138). Moreover, type 1 diabetes is associated with decreased white-matter volume of the brain and diminished cognitive performance in particular in patients with retinopathy (139). Microvascular complications are also thought to play a role in the development of cognitive decline in patients with type 2 diabetes, but studies that have specifically examined this association are scarce. […] Currently there are no established specific treatment measures to prevent or ameliorate cognitive impairments in patients with diabetes.”

“Clinicians should be aware of the fact that cognitive decrements are relatively more common among patients with diabetes. […] it is important to note that cognitive complaints as spontaneously expressed by the patient are often a poor indicator of the severity of cognitive decrements. People with moderate disturbances may express marked complaints, while people with marked disturbances of cognition often do not complain at all. […] Diabetes is generally associated with relatively mild impairments, mainly in attention, memory, information-processing speed, and executive function. Rapid cognitive decline or severe cognitive impairment, especially in persons under the age of 60 is indicative of other underlying pathology. Potentially treatable causes of cognitive decline such as depression should be excluded. People who are depressed often present with complaints of concentration or memory.”

“Insulin resistance increases with age, and the organism maintains normal glucose levels as long as it can produce enough insulin (hyperinsulinemia). Some individuals are less capable than others to mount sustained hyperinsulinemia and will develop glucose intolerance and T2D (23). Other individuals with insulin resistance will maintain normal glucose levels at the expense of hyperinsulinemia but their pancreas will eventually “burn out,” will not be able to sustain hyperinsulinemia, and will develop glucose intolerance and diabetes (23). Others will continue having insulin resistance, may have or not have glucose intolerance, will not develop diabetes, but will have hyperinsulinemia and suffer its consequences. […] Elevations of adiposity result in insulin resistance, causing the pancreas to increase insulin to abnormal levels to sustain normal glucose, and if and when the pancreas can no longer sustain hyperinsulinemia, glucose intolerance and diabetes will ensue. However, the overlap between these processes is not complete (26). Not all persons with higher adiposity will develop insulin resistance and hyperinsulinemia, but most will. Not all persons with insulin resistance and hyperinsulinemia will develop glucose intolerance and diabetes, and this depends on genetic and other susceptibility factors that are not completely understood (25, 26). Some adults develop diabetes without going through insulin resistance and hyperinsulinemia, but it is thought that most will. The susceptibility to adiposity, that is, the risk of developing the above-described sequence in response to adiposity, varies by gender (4) and particularly by ethnicity. […] Chinese and Southeast Asians are more susceptible than Europeans to developing insulin resistance with comparable increases of adiposity (2).”

There is very strong evidence that adiposity, hyperinsulinemia, and T2D are related to cognitive impairment syndromes, whether AD [Alzheimer’s Disease], VD [Vascular Dementia], or MCI [Mild Cognitive Impairment], and whether the main mechanism is cerebrovascular disease or non-vascular mechanisms. However, more evidence is needed to establish causation. If the relation between these conditions and dementia were to be causal, the public health implications are enormous. […] Diabetes mellitus affects about 20% of adults older than 65 years of age […] two-thirds of the adult population in the United States are overweight or obese, and the short-term trend is for this to worsen. These trends are also being observed worldwide. […] We estimated that in New York City the presence of diabetes or hyperinsulinemia in elderly people could account for 39% of cases of AD (78).”

Psychiatric illnesses in general may be more common among persons with diabetes than in community-based samples, specifically affective and anxiety-related disorders (4). Persons with diabetes are twice as likely to have depression as non-diabetic persons (5). A review of 20 studies on the comorbidity of depression and diabetes found that the average prevalence was about 15%, and ranged from 8.5 to 40%, three times the rate of depressive disorders found in the general adult population of the United States (4–7). The rates of clinically significant depressive symptoms among persons with diabetes are even higher – ranging from 21.8 to 60.0% (8). Recent studies have indicated that persons with type II diabetes, accompanied by either major or minor depression, have significantly higher mortality rates than non-depressed persons with diabetes (9–10) […] A recent meta-analysis reported that patients with type 2 diabetes have a 2-fold increased risk of depression compared to non-diabetic persons (142). The prevalence of major depressive disorder in patients with type 2 diabetes was estimated at 11% and depressive symptoms were observed in 31% of the patients.” (As should be obvious from the above quotes the range of estimates vary a lot here, but the estimates tend to be high – US.)

Depression is an important risk factor for cardiovascular disease (Glassman, Maj & Sartorius is a decent book on these topics), and diabetes is also an established risk factor. Might this not lead to a hypothesis that diabetics who are depressed may do particularly poorly, with higher mortality rates and so on? Yes. …and it seems that this is also what people tend to find when they look at this stuff:

Persons with diabetes and depressive symptoms have mortality rates nearly twice as high as persons with diabetes and no depressive symptomatology (9). Persons with co-occurring medical illness and depression also have higher health care utilization leading to higher direct and indirect health care costs (12–13) […]. A meta-analysis of the relationship between depression and diabetes (types I and II) indicated that an increase in the number of depressive symptoms is associated with an increase in the severity and number of diabetic complications, including retinopathy, neuropathy, and nephropathy (15–17). Compared to persons with either diabetes or depression alone, individuals with co-occurring diabetes and depression have shown poorer adherence to dietary and physical activity recommendations, decreased adherence to hypoglycemic medication regimens, higher health care costs, increases in HgbA1c levels, poorer glycemic control, higher rates of retinopathy, and macrovascular complications such as stroke and myocardial infarction, higher ambulatory care use, and use of prescriptions (14, 18–22). Diabetes and depressive symptoms have been shown to have strong independent effects on physical functioning, and individuals experiencing either of these conditions will have worse functional outcomes than those with neither or only one condition (19–20). Nearly all of diabetes management is conducted by the patient and those with co-occurring depression may have poorer outcomes and increased risk of complications due to less adherence to glucose, diet, and medication regimens […] There is some evidence that treatment of depression with antidepressant and/or cognitive-behavioral therapies can improve glycemic control and glucose regulation without any change in the treatment for diabetes (27, 28) […] One important finding is [also] that treatment of depression seems to be able to halt atrophy of the hippocampus and may even lead to stimulation of neurogenesis of hippocampal cells (86).”

Diabetic neuropathy is a severe, disabling chronic condition that affects a significant number of individuals with diabetes. Long considered a disease of the peripheral nervous system, there is mounting evidence of central nervous system involvement. Recent advances in neuroimaging methods have led to a better understanding and refinement of how diabetic neuropathy affects the central nervous system. […] spinal cord atrophy is an early process being present not only in established-DPN [diabetic peripheral neuropathy] but also even in subjects with relatively modest impairments of nerve function (subclinical-DPN) […] findings […] show that the neuropathic process in diabetes is not confined to the peripheral nerve and does involve the spinal cord. Worryingly, this occurs early in the neuropathic process. Even at the early DPN stage, extensive and perhaps even irreversible damage may have occurred. […] it is likely that the insult of diabetes is generalised, concomitantly affecting the PNS and CNS. […] It is noteworthy that a variety of therapeutic interventions specifically targeted at peripheral nerve damage in DPN have thus far been ineffective, and it is possible that this may in part be due to inadequate appreciation of the full extent of CNS involvement in DPN.

Interestingly, if the CNS is also involved in the pathogenesis of (‘human’) diabetic neuropathy it may have some relevance to the complaint that some methods of diabetes-induction in animal models cause (secondary) damage to central structures in animal models – a complaint which I’ve previously made a note of e.g. in the context of my coverage of Horowitz & Samson’s book. The relevance of this depends quite a bit on whether it’s the same central structures that are affected in the animal models and in humans. It probably isn’t. These guys also discuss this stuff in some detail, though I won’t go into too much detail here. Some observations on related topics are however worth including here:

“Several studies examining behavioral learning have shown progressive deficits in diabetic rodents, whereas simple avoidance tasks are preserved. Impaired spatial learning and memory as assessed by the Morris water maze paradigm occur progressively in both the spontaneously diabetic BB/Worrat and STZ-induced diabetic rodents (1, 11, 12, 22, 41, 42). The cognitive components reflected by impaired Morris water maze performances involve problem-solving, enhanced attention and storage, and retrieval of information (43). […] Observations regarding cognition and plasticity in models characterized by hyperglycemia and insulin deficiency (i.e., alloxan or STZ-diabetes, BB/Wor rats, NOD-mice), often referred to as models of type 1 diabetes, are quite consistent. With respect to clinical relevance, it should be noted that the level of glycemia in these models markedly exceeds that observed in patients. Moreover, changes in cognition as observed in these models are much more rapid and severe than in adult patients with type 1 diabetes […], even if the relatively shorter lifespan of rodents is taken into account. […] In my view these models of “type 1 diabetes” may help to understand the pathophysiology of the effects of severe chronic hyperglycemia–hypoinsulinemia on the brain, but mimic the impact of type 1 diabetes on the brain in humans only to a limited extent.”

“Abnormalities in cognition and plasticity have also been noted in the majority of models characterized by insulin resistance, hyperinsulinemia, and (modest) hyperglycemia (e.g., Zucker fa/fa rat, Diabetic Zucker rat, db/db mouse, GK rat, OLETF rat), often referred to as models of type 2 diabetes. With regard to clinical relevance, it is important to note that although the endocrinological features of these models do mimic certain aspects of type 2 diabetes, the genetic defect that underlies each of them is not the primary defect encountered in humans with type 2 diabetes. Some of the genetic abnormalities that lead to a “diabetic phenotype” may also have a direct impact on the brain. […] some studies using these models report abnormalities in cognition and plasticity, even in the absence of hyperglycemia […] In addition, in the majority of available models insulin resistance and associated metabolic abnormalities develop at a relatively early age. Although this is practical for research purposes it needs to be acknowledged that type 2 diabetes is typically a disease of older age in humans. […] It is therefore still too early to determine the clinical significance of the available models in understanding the impact of type 2 diabetes on the brain. Further efforts into the development of a valid model are warranted.”

[A] key problem in clinical studies is the complexity and multifactorial nature of cerebral complications in relation to diabetes. Metabolic factors in patients (e.g., glucose levels, insulin levels, insulin sensitivity) are strongly interrelated and related to other factors that may affect the brain (e.g., blood pressure, lipids, inflammation, oxidative stress). Derangements in these factors in the periphery and the brain may be dissociated, for example, through the role of the blood–brain barrier, or adaptations of transport across this barrier, or through differences in receptor functions and post-receptor signaling cascades in the periphery and the brain. The different forms of treatments that patients receive add to the complexity. A key contribution of animal studies may be to single out individual components and study them in isolation or in combination with a limited number of other factors in a controlled fashion.

October 9, 2017 Posted by | Books, Cardiology, Diabetes, Epidemiology, Medicine, Neurology, Pharmacology | Leave a comment

Physical chemistry

This is a good book, I really liked it, just as I really liked the other book in the series which I read by the same author, the one about the laws of thermodynamics (blog coverage here). I know much, much more about physics than I do about chemistry and even though some of it was review I learned a lot from this one. Recommended, certainly if you find the quotes below interesting. As usual, I’ve added some observations from the book and some links to topics/people/etc. covered/mentioned in the book below.

Some quotes:

“Physical chemists pay a great deal of attention to the electrons that surround the nucleus of an atom: it is here that the chemical action takes place and the element expresses its chemical personality. […] Quantum mechanics plays a central role in accounting for the arrangement of electrons around the nucleus. The early ‘Bohr model’ of the atom, […] with electrons in orbits encircling the nucleus like miniature planets and widely used in popular depictions of atoms, is wrong in just about every respect—but it is hard to dislodge from the popular imagination. The quantum mechanical description of atoms acknowledges that an electron cannot be ascribed to a particular path around the nucleus, that the planetary ‘orbits’ of Bohr’s theory simply don’t exist, and that some electrons do not circulate around the nucleus at all. […] Physical chemists base their understanding of the electronic structures of atoms on Schrödinger’s model of the hydrogen atom, which was formulated in 1926. […] An atom is often said to be mostly empty space. That is a remnant of Bohr’s model in which a point-like electron circulates around the nucleus; in the Schrödinger model, there is no empty space, just a varying probability of finding the electron at a particular location.”

“No more than two electrons may occupy any one orbital, and if two do occupy that orbital, they must spin in opposite directions. […] this form of the principle [the Pauli exclusion principleUS] […] is adequate for many applications in physical chemistry. At its very simplest, the principle rules out all the electrons of an atom (other than atoms of one-electron hydrogen and two-electron helium) having all their electrons in the 1s-orbital. Lithium, for instance, has three electrons: two occupy the 1s orbital, but the third cannot join them, and must occupy the next higher-energy orbital, the 2s-orbital. With that point in mind, something rather wonderful becomes apparent: the structure of the Periodic Table of the elements unfolds, the principal icon of chemistry. […] The first electron can enter the 1s-orbital, and helium’s (He) second electron can join it. At that point, the orbital is full, and lithium’s (Li) third electron must enter the next higher orbital, the 2s-orbital. The next electron, for beryllium (Be), can join it, but then it too is full. From that point on the next six electrons can enter in succession the three 2p-orbitals. After those six are present (at neon, Ne), all the 2p-orbitals are full and the eleventh electron, for sodium (Na), has to enter the 3s-orbital. […] Similar reasoning accounts for the entire structure of the Table, with elements in the same group all having analogous electron arrangements and each successive row (‘period’) corresponding to the next outermost shell of orbitals.”

“[O]n crossing the [Periodic] Table from left to right, atoms become smaller: even though they have progressively more electrons, the nuclear charge increases too, and draws the clouds in to itself. On descending a group, atoms become larger because in successive periods new outermost shells are started (as in going from lithium to sodium) and each new coating of cloud makes the atom bigger […] the ionization energy [is] the energy needed to remove one or more electrons from the atom. […] The ionization energy more or less follows the trend in atomic radii but in an opposite sense because the closer an electron lies to the positively charged nucleus, the harder it is to remove. Thus, ionization energy increases from left to right across the Table as the atoms become smaller. It decreases down a group because the outermost electron (the one that is most easily removed) is progressively further from the nucleus. […] the electron affinity [is] the energy released when an electron attaches to an atom. […] Electron affinities are highest on the right of the Table […] An ion is an electrically charged atom. That charge comes about either because the neutral atom has lost one or more of its electrons, in which case it is a positively charged cation […] or because it has captured one or more electrons and has become a negatively charged anion. […] Elements on the left of the Periodic Table, with their low ionization energies, are likely to lose electrons and form cations; those on the right, with their high electron affinities, are likely to acquire electrons and form anions. […] ionic bonds […] form primarily between atoms on the left and right of the Periodic Table.”

“Although the Schrödinger equation is too difficult to solve for molecules, powerful computational procedures have been developed by theoretical chemists to arrive at numerical solutions of great accuracy. All the procedures start out by building molecular orbitals from the available atomic orbitals and then setting about finding the best formulations. […] Depictions of electron distributions in molecules are now commonplace and very helpful for understanding the properties of molecules. It is particularly relevant to the development of new pharmacologically active drugs, where electron distributions play a central role […] Drug discovery, the identification of pharmacologically active species by computation rather than in vivo experiment, is an important target of modern computational chemistry.”

Work […] involves moving against an opposing force; heat […] is the transfer of energy that makes use of a temperature difference. […] the internal energy of a system that is isolated from external influences does not change. That is the First Law of thermodynamics. […] A system possesses energy, it does not possess work or heat (even if it is hot). Work and heat are two different modes for the transfer of energy into or out of a system. […] if you know the internal energy of a system, then you can calculate its enthalpy simply by adding to U the product of pressure and volume of the system (H = U + pV). The significance of the enthalpy […] is that a change in its value is equal to the output of energy as heat that can be obtained from the system provided it is kept at constant pressure. For instance, if the enthalpy of a system falls by 100 joules when it undergoes a certain change (such as a chemical reaction), then we know that 100 joules of energy can be extracted as heat from the system, provided the pressure is constant.”

“In the old days of physical chemistry (well into the 20th century), the enthalpy changes were commonly estimated by noting which bonds are broken in the reactants and which are formed to make the products, so A → B might be the bond-breaking step and B → C the new bond-formation step, each with enthalpy changes calculated from knowledge of the strengths of the old and new bonds. That procedure, while often a useful rule of thumb, often gave wildly inaccurate results because bonds are sensitive entities with strengths that depend on the identities and locations of the other atoms present in molecules. Computation now plays a central role: it is now routine to be able to calculate the difference in energy between the products and reactants, especially if the molecules are isolated as a gas, and that difference easily converted to a change of enthalpy. […] Enthalpy changes are very important for a rational discussion of changes in physical state (vaporization and freezing, for instance) […] If we know the enthalpy change taking place during a reaction, then provided the process takes place at constant pressure we know how much energy is released as heat into the surroundings. If we divide that heat transfer by the temperature, then we get the associated entropy change in the surroundings. […] provided the pressure and temperature are constant, a spontaneous change corresponds to a decrease in Gibbs energy. […] the chemical potential can be thought of as the Gibbs energy possessed by a standard-size block of sample. (More precisely, for a pure substance the chemical potential is the molar Gibbs energy, the Gibbs energy per mole of atoms or molecules.)”

“There are two kinds of work. One kind is the work of expansion that occurs when a reaction generates a gas and pushes back the atmosphere (perhaps by pressing out a piston). That type of work is called ‘expansion work’. However, a chemical reaction might do work other than by pushing out a piston or pushing back the atmosphere. For instance, it might do work by driving electrons through an electric circuit connected to a motor. This type of work is called ‘non-expansion work’. […] a change in the Gibbs energy of a system at constant temperature and pressure is equal to the maximum non-expansion work that can be done by the reaction. […] the link of thermodynamics with biology is that one chemical reaction might do the non-expansion work of building a protein from amino acids. Thus, a knowledge of the Gibbs energies changes accompanying metabolic processes is very important in bioenergetics, and much more important than knowing the enthalpy changes alone (which merely indicate a reaction’s ability to keep us warm).”

“[T]he probability that a molecule will be found in a state of particular energy falls off rapidly with increasing energy, so most molecules will be found in states of low energy and very few will be found in states of high energy. […] If the temperature is low, then the distribution declines so rapidly that only the very lowest levels are significantly populated. If the temperature is high, then the distribution falls off very slowly with increasing energy, and many high-energy states are populated. If the temperature is zero, the distribution has all the molecules in the ground state. If the temperature is infinite, all available states are equally populated. […] temperature […] is the single, universal parameter that determines the most probable distribution of molecules over the available states.”

“Mixing adds disorder and increases the entropy of the system and therefore lowers the Gibbs energy […] In the absence of mixing, a reaction goes to completion; when mixing of reactants and products is taken into account, equilibrium is reached when both are present […] Statistical thermodynamics, through the Boltzmann distribution and its dependence on temperature, allows physical chemists to understand why in some cases the equilibrium shifts towards reactants (which is usually unwanted) or towards products (which is normally wanted) as the temperature is raised. A rule of thumb […] is provided by a principle formulated by Henri Le Chatelier […] that a system at equilibrium responds to a disturbance by tending to oppose its effect. Thus, if a reaction releases energy as heat (is ‘exothermic’), then raising the temperature will oppose the formation of more products; if the reaction absorbs energy as heat (is ‘endothermic’), then raising the temperature will encourage the formation of more product.”

“Model building pervades physical chemistry […] some hold that the whole of science is based on building models of physical reality; much of physical chemistry certainly is.”

“For reasonably light molecules (such as the major constituents of air, N2 and O2) at room temperature, the molecules are whizzing around at an average speed of about 500 m/s (about 1000 mph). That speed is consistent with what we know about the propagation of sound, the speed of which is about 340 m/s through air: for sound to propagate, molecules must adjust their position to give a wave of undulating pressure, so the rate at which they do so must be comparable to their average speeds. […] a typical N2 or O2 molecule in air makes a collision every nanosecond and travels about 1000 molecular diameters between collisions. To put this scale into perspective: if a molecule is thought of as being the size of a tennis ball, then it travels about the length of a tennis court between collisions. Each molecule makes about a billion collisions a second.”

“X-ray diffraction makes use of the fact that electromagnetic radiation (which includes X-rays) consists of waves that can interfere with one another and give rise to regions of enhanced and diminished intensity. This so-called ‘diffraction pattern’ is characteristic of the object in the path of the rays, and mathematical procedures can be used to interpret the pattern in terms of the object’s structure. Diffraction occurs when the wavelength of the radiation is comparable to the dimensions of the object. X-rays have wavelengths comparable to the separation of atoms in solids, so are ideal for investigating their arrangement.”

“For most liquids the sample contracts when it freezes, so […] the temperature does not need to be lowered so much for freezing to occur. That is, the application of pressure raises the freezing point. Water, as in most things, is anomalous, and ice is less dense than liquid water, so water expands when it freezes […] when two gases are allowed to occupy the same container they invariably mix and each spreads uniformly through it. […] the quantity of gas that dissolves in any liquid is proportional to the pressure of the gas. […] When the temperature of [a] liquid is raised, it is easier for a dissolved molecule to gather sufficient energy to escape back up into the gas; the rate of impacts from the gas is largely unchanged. The outcome is a lowering of the concentration of dissolved gas at equilibrium. Thus, gases appear to be less soluble in hot water than in cold. […] the presence of dissolved substances affects the properties of solutions. For instance, the everyday experience of spreading salt on roads to hinder the formation of ice makes use of the lowering of freezing point of water when a salt is present. […] the boiling point is raised by the presence of a dissolved substance [whereas] the freezing point […] is lowered by the presence of a solute.”

“When a liquid and its vapour are present in a closed container the vapour exerts a characteristic pressure (when the escape of molecules from the liquid matches the rate at which they splash back down into it […][)] This characteristic pressure depends on the temperature and is called the ‘vapour pressure’ of the liquid. When a solute is present, the vapour pressure at a given temperature is lower than that of the pure liquid […] The extent of lowering is summarized by yet another limiting law of physical chemistry, ‘Raoult’s law’ [which] states that the vapour pressure of a solvent or of a component of a liquid mixture is proportional to the proportion of solvent or liquid molecules present. […] Osmosis [is] the tendency of solvent molecules to flow from the pure solvent to a solution separated from it by a [semi-]permeable membrane […] The entropy when a solute is present in a solvent is higher than when the solute is absent, so an increase in entropy, and therefore a spontaneous process, is achieved when solvent flows through the membrane from the pure liquid into the solution. The tendency for this flow to occur can be overcome by applying pressure to the solution, and the minimum pressure needed to overcome the tendency to flow is called the ‘osmotic pressure’. If one solution is put into contact with another through a semipermeable membrane, then there will be no net flow if they exert the same osmotic pressures and are ‘isotonic’.”

“Broadly speaking, the reaction quotient [‘Q’] is the ratio of concentrations, with product concentrations divided by reactant concentrations. It takes into account how the mingling of the reactants and products affects the total Gibbs energy of the mixture. The value of Q that corresponds to the minimum in the Gibbs energy […] is called the equilibrium constant and denoted K. The equilibrium constant, which is characteristic of a given reaction and depends on the temperature, is central to many discussions in chemistry. When K is large (1000, say), we can be reasonably confident that the equilibrium mixture will be rich in products; if K is small (0.001, say), then there will be hardly any products present at equilibrium and we should perhaps look for another way of making them. If K is close to 1, then both reactants and products will be abundant at equilibrium and will need to be separated. […] Equilibrium constants vary with temperature but not […] with pressure. […] van’t Hoff’s equation implies that if the reaction is strongly exothermic (releases a lot of energy as heat when it takes place), then the equilibrium constant decreases sharply as the temperature is raised. The opposite is true if the reaction is strongly endothermic (absorbs a lot of energy as heat). […] Typically it is found that the rate of a reaction [how fast it progresses] decreases as it approaches equilibrium. […] Most reactions go faster when the temperature is raised. […] reactions with high activation energies proceed slowly at low temperatures but respond sharply to changes of temperature. […] The surface area exposed by a catalyst is important for its function, for it is normally the case that the greater that area, the more effective is the catalyst.”


John Dalton.
Atomic orbital.
Electron configuration.
S,p,d,f orbitals.
Computational chemistry.
Atomic radius.
Covalent bond.
Gilbert Lewis.
Valence bond theory.
Molecular orbital theory.
Orbital hybridisation.
Bonding and antibonding orbitals.
Schrödinger equation.
Density functional theory.
Chemical thermodynamics.
Laws of thermodynamics/Zeroth law/First law/Second law/Third Law.
Conservation of energy.
Spontaneous processes.
Rudolf Clausius.
Chemical equilibrium.
Heat capacity.
Statistical thermodynamics/statistical mechanics.
Boltzmann distribution.
State of matter/gas/liquid/solid.
Perfect gas/Ideal gas law.
Robert Boyle/Joseph Louis Gay-Lussac/Jacques Charles/Amedeo Avogadro.
Equation of state.
Kinetic theory of gases.
Van der Waals equation of state.
Maxwell–Boltzmann distribution.
Thermal conductivity.
Nuclear magnetic resonance.
Debye–Hückel equation.
Ionic solids.
Supercritical fluid.
Liquid crystal.
Benoît Paul Émile Clapeyron.
Phase (matter)/phase diagram/Gibbs’ phase rule.
Ideal solution/regular solution.
Henry’s law.
Chemical kinetics.
Rate equation/First order reactions/Second order reactions.
Rate-determining step.
Arrhenius equation.
Collision theory.
Diffusion-controlled and activation-controlled reactions.
Transition state theory.
Redox reactions.
Electrochemical cell.
Fuel cell.
Reaction dynamics.
Spectroscopy/emission spectroscopy/absorption spectroscopy/Raman spectroscopy.
Raman effect.
Magnetic resonance imaging.
Fourier-transform spectroscopy.
Electron paramagnetic resonance.
Mass spectrum.
Electron spectroscopy for chemical analysis.
Scanning tunneling microscope.

October 5, 2017 Posted by | Biology, Books, Chemistry, Pharmacology, Physics | Leave a comment