A few diabetes papers of interest

i. Glycated Hemoglobin and All-Cause and Cause-Specific Mortality in Singaporean Chinese Without Diagnosed Diabetes: The Singapore Chinese Health Study.

“Previous studies have reported that elevated levels of HbA1c below the diabetes threshold (<6.5%) are associated with an increased risk for cardiovascular morbidity and mortality (312). Yet, this research base is not comprehensive, and data from Chinese populations are scant, especially in those without diabetes. This gap in the literature is important since Southeast Asian populations are experiencing epidemic rates of type 2 diabetes and related comorbidities with a substantial global health impact (1316).

Overall, there are few cohort studies that have examined the etiologic association between HbA1c levels and all-cause and cause-specific mortality. There is even lesser insight on the nature of the relationship between HbA1c and significant clinical outcomes in Southeast Asian populations. Therefore, we examined the association between HbA1c and all-cause and cause-specific mortality in the Singapore Chinese Health Study (SCHS).”

“The design of the SCHS has been previously summarized (17). Briefly, the cohort was drawn from men and women, aged 45–74 years, who belonged to one of the major dialect groups (Hokkien or Cantonese) of Chinese in Singapore. […] Between April 1993 and December 1998, 63,257 individuals completed an in-person interview that included questions on usual diet, demographics, height and weight, use of tobacco, usual physical activity, menstrual and reproductive history (women only), medical history including history of diabetes diagnosis by a physician, and family history of cancer. […] At the follow-up interview (F1), which occurred in 1999–2004, subjects were asked to update their baseline interview information. […] The study population derived from 28,346 participants of the total 54,243 who were alive and participated at F1, who provided consent at F1 to collect subsequent blood samples (a consent rate of ∼65%). The participants for this study were a random selection of individuals from the full study population who did not report a history of diabetes or CVD at the baseline or follow-up interview and reported no history of cancer.”

“During 74,890 person-years of follow-up, there were 888 total deaths, of which 249 were due to CVD, 388 were due to cancer, and 169 were recorded as respiratory mortality. […] There was a positive association between HbA1c and age, BMI, and prevalence of self-reported hypertension, while an inverse association was observed between educational attainment and HbA1c. […] The crude mortality rate was 1,186 deaths per 100,000 person-years. The age- and sex-standardized mortality rates for all-cause, CVD, and cerebrovascular each showed a J-shaped pattern according to HbA1c level. The CHD and cancer mortality rates were higher for HbA1c ≥6.5% (≥48 mmol/mol) and otherwise displayed no apparent pattern. […] There was no association between any level of HbA1c and respiratory causes of death.”

“Chinese men and women with no history of cancer, reported diabetes, or CVD with an HbA1c level ≥6.5% (≥48 mmol/mol) were at a significant increased risk of mortality during follow-up relative to their peers with an HbA1c of 5.4–5.6% (36–38 mmol/mol). No other range of HbA1c was significantly associated with risk of mortality during follow-up, and in secondary analyses, when the HbA1c level ≥6.5% (≥48 mmol/mol) was divided into four categories, this increased risk was observed in all four categories; thus, these data represent a clear threshold association between HbA1c and mortality in this population. These results are consistent with previous prospective cohort studies identifying chronically high HbA1c, outside of diabetes, to be associated with increased risk for all-cause and CVD-related mortality (312,22).”

“Hyperglycemia is a known risk factor for CVD, not limited to individuals with diabetes. This may be in part due to the vascular damage caused by oxidative stress in periods of hypo- and hyperglycemia (23,24). For individuals with impaired fasting glucose and impaired glucose tolerance, increased oxidative stress and endothelial dysfunction are present before the onset of diabetes (25). The association between chronically high levels of HbA1c and development of and death from cancer is not as well defined (9,2630). Abnormal metabolism may play a role in cancer development and death. This is important, considering cancer is the leading cause of death in Singapore for adults 15–59 years of age (31). Increased risk for cancer mortality was found in individuals with impaired glucose tolerance (30). […] Hyperinsulinemia and IGF-I are associated with increased cancer risk, possibly through mitogenic effects and tumor formation (27,28,37). This is the basis for the insulin-cancer hypothesis. Simply put, chronic levels of hyperinsulinemia reduce the production of IGF binding proteins 1 and 2. The absence of these proteins results in excess bioactive IGF-I, supporting tumor development (38). Chronic hyperglycemia, indicating high levels of insulin and IGF-I, may explain inhibition of cell apoptosis, increased cell proliferation, and increased cancer risk (39).”

ii. The Cross-sectional and Longitudinal Associations of Diabetic Retinopathy With Cognitive Function and Brain MRI Findings: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial.

“Brain imaging studies suggest that type 2 diabetes–related microvascular disease may affect the central nervous system in addition to its effects on other organs, such as the eye and kidney. Histopathological evidence indicates that microvascular disease in the brain can lead to white matter lesions (WMLs) visible with MRI of the brain (1), and risk for them is often increased by type 2 diabetes (26). Type 2 diabetes also has recently been associated with lower brain volume, particularly gray matter volume (79).

The association between diabetic retinopathy and changes in brain tissue is of particular interest because retinal and cerebral small vessels have similar anatomy, physiology, and embryology (10). […] the preponderance of evidence suggests diabetic retinopathy is associated with increased WML burden (3,1214), although variation exists. While cross-sectional studies support a correlation between diabetic retinopathy and WMLs (2,3,6,15), diabetic retinopathy and brain atrophy (16), diabetic retinopathy and psychomotor speed (17,18), and psychomotor speed and WMLs (5,19,20), longitudinal evidence demonstrating the assumed sequence of disease development, for example, vascular damage of eye and brain followed by cognitive decline, is lacking.

Using Action to Control Cardiovascular Risk in Diabetes (ACCORD) data, in which a subset of participants received longitudinal measurements of diabetic retinopathy, cognition, and MRI variables, we analyzed the 1) cross-sectional associations between diabetic retinopathy and evidence of brain microvascular disease and 2) determined whether baseline presence or severity of diabetic retinopathy predicts 20- or 40-month changes in cognitive performance or brain microvascular disease.”

“The ACCORD trial (21) was a multicenter randomized trial examining the effects of intensive glycemic control, blood pressure, and lipids on cardiovascular disease events. The 10,251 ACCORD participants were aged 40–79 years, had poorly controlled type 2 diabetes (HbA1c > 7.5% [58.5 mmol/mol]), and had or were at high risk for cardiovascular disease. […] The ACCORD-Eye sample comprised 3,472 participants who did not report previous vitrectomy or photocoagulation surgery for proliferative diabetic retinopathy at baseline […] ACCORD-MIND included a subset of 2,977 ACCORD participants who completed a 30-min cognitive testing battery, 614 of whom also had useable scans from the MRI substudy (23,24). […] ACCORD-MIND had visits at three time points: baseline, 20 months, and 40 months. MRI of the brain was completed at baseline and the 40-month time point.”

“Baseline diabetic retinopathy was associated with more rapid 40-month declines in DSST and MMSE [Mini-Mental State Examination] when adjusting for demographics and lifestyle factors in model 1 […]. Moreover, increasing severity of diabetic retinopathy was associated with increased amounts of decline in DSST [Digit Symbol Substitution Test] performance (−1.30, −1.76, and −2.81 for no, mild, and moderate/severe NPDR, respectively; P = 0.003) […Be careful about how to interpret that p-value – see below, US] . The associations remained virtually unchanged after further adjusting for vascular and diabetes risk factors, depression, and visual acuity using model 2.”

“This longitudinal study provides new evidence that diabetic retinopathy is associated with future cognitive decline in persons with type 2 diabetes and confirms the finding from the Edinburgh Type 2 Diabetes Study derived from cross-sectional data that lifetime cognitive decline is associated with diabetic retinopathy (32). We found that the presence of diabetic retinopathy, independent of visual acuity, predicts greater declines in global cognitive function measured with the MMSE and that the magnitude of decline in processing speed measured with the DSST increased with increasing severity of baseline diabetic retinopathy. The association with psychomotor speed is consistent with prior cross-sectional findings in community-based samples of middle-aged (18) and older adults (17), as well as prospective studies of a community-based sample of middle-aged adults (33) and patients with type 1 diabetes (34) showing that retinopathy with different etiologies predicted a subsequent decline in psychomotor speed. This study extends these findings to patients with type 2 diabetes.”

“we tested a number of different associations but did not correct P values for multiple testing” [Aargh!, US.]

iii. Incidence of Remission in Adults With Type 2 Diabetes: The Diabetes & Aging Study.

(Note to self before moving on to the paper: these people identified type 1 diabetes by self-report or diabetes onset at <30 years of age, treated with insulin only and never treated with oral agents).

“It is widely believed that type 2 diabetes is a chronic progressive condition, which at best can be controlled, but never cured (1), and that once treatment with glucose-lowering medication is initiated, it is required indefinitely and is intensified over time (2,3). However, a growing body of evidence from clinical trials and case-control studies (46) has reported the remission of type 2 diabetes in certain populations, most notably individuals who received bariatric surgery. […] Despite the clinical relevance and importance of remission, little is known about the incidence of remission in community settings (11,12). Studies to date have focused largely on remission after gastric bypass or relied on data from clinical trials, which have limited generalizability. Therefore, we conducted a retrospective cohort study to describe the incidence rates and variables associated with remission among adults with type 2 diabetes who received usual care, excluding bariatric surgery, in a large, ethnically diverse population. […] 122,781 individuals met our study criteria, yielding 709,005 person-years of total follow-up time.”

“Our definitions of remission were based on the 2009 ADA consensus statement (10). “Partial remission” of diabetes was defined as having two or more consecutive subdiabetic HbA1c measurements, all of which were in the range of 5.7–6.4% [39–46 mmol/mol] over a period of at least 12 months. “Complete remission” was defined as having two or more consecutive normoglycemic HbA1c measurements, all of which were <5.7% [<39 mmol/mol] over a period of at least 12 months. “Prolonged remission” was defined as having two or more consecutive normoglycemic HbA1c measurements, all of which were <5.7% [<39 mmol/mol] over a period of at least 60 months. Each definition of remission requires the absence of pharmacologic treatment during the defined observation period.”

“The average age of participants was 62 years, 47.1% were female, and 51.6% were nonwhite […]. The mean (SD) interval between HbA1c tests in the remission group was 256 days (139 days). The mean interval (SD) between HbA1c tests among patients not in the remission group was 212 days (118 days). The median time since the diagnosis of diabetes in our cohort was 5.9 years, and the average baseline HbA1c level was 7.4% [57 mmol/mol]. The 18,684 individuals (15.2%) in the subset with new-onset diabetes, defined as ≤2 years since diagnosis, were younger, were more likely to have their diabetes controlled by diet, and had fewer comorbidities […] The incidence densities of partial, complete, and prolonged remission in the full cohort were 2.8 (95% CI 2.6–2.9), 0.24 (95% CI 0.20–0.28), and 0.04 (95% CI 0.01–0.06) cases per 1,000 person-years, respectively […] The 7-year cumulative incidences of partial, complete, and prolonged remission were 1.5% (95% CI 1.4–1.5%), 0.14% (95% CI 0.12–0.16%), and 0.01% (95% CI 0.003–0.02%), respectively. The 7-year cumulative incidence of any remission decreased with longer time since diagnosis from a high of 4.6% (95% CI 4.3–4.9%) for individuals diagnosed with diabetes in the past 2 years to a low of 0.4% (95% CI 0.3–0.5%) in those diagnosed >10 years ago. The 7-year cumulative incidence of any remission was much lower for individuals using insulin (0.05%; 95% CI 0.03–0.1%) or oral agents (0.3%; 95% CI 0.2–0.3%) at baseline compared with diabetes patients not using medication at baseline (12%; 95% CI 12–13%).”

“In this large cohort of insured adults with type 2 diabetes not treated with bariatric surgery, we found that 1.5% of individuals with recent evidence of clinical diabetes achieved at least partial remission over a 7-year period. If these results were generalized to the 25.6 million U.S. adults living with type 2 diabetes in 2010 (25), they would suggest that 384,000 adults could experience remission over the next 7 years. However, the rate of prolonged remission was extremely rare (0.007%), translating into only 1,800 adults in the U.S. experiencing remission lasting at least 5 years. To provide context, 1.7% of the cohort died, while only 0.8% experienced any level of remission, during the calendar year 2006. Thus, the chances of dying were higher than the chances of any remission. […] Although remission of type 2 diabetes is uncommon, it does occur in patients who have not undergone surgical interventions. […] Our analysis shows that remission is rare and variable. The likelihood of remission is more common among individuals with early-onset diabetes and those not treated with glucose-lowering medications at the point of diabetes diagnosis. Although rare, remission can also occur in individuals with more severe diabetes and those previously treated with insulin.”

iv. Blood pressure control for diabetic retinopathy (Cochrane review).

“Diabetic retinopathy is a common complication of diabetes and a leading cause of visual impairment and blindness. Research has established the importance of blood glucose control to prevent development and progression of the ocular complications of diabetes. Simultaneous blood pressure control has been advocated for the same purpose, but findings reported from individual studies have supported varying conclusions regarding the ocular benefit of interventions on blood pressure. […] The primary aim of this review was to summarize the existing evidence regarding the effect of interventions to control or reduce blood pressure levels among diabetics on incidence and progression of diabetic retinopathy, preservation of visual acuity, adverse events, quality of life, and costs. A secondary aim was to compare classes of anti-hypertensive medications with respect to the same outcomes.”

“We included 15 RCTs, conducted primarily in North America and Europe, that had enrolled 4157 type 1 and 9512 type 2 diabetic participants, ranging from 16 to 2130 participants in individual trials. […] Study designs, populations, interventions, and lengths of follow-up (range one to nine years) varied among the included trials. Overall, the quality of the evidence for individual outcomes was low to moderate.”

“The evidence from these trials supported a benefit of more intensive blood pressure control intervention with respect to 4- to 5-year incidence of diabetic retinopathy (estimated risk ratio (RR) 0.80; 95% confidence interval (CI) 0.71 to 0.92) and the combined outcome of incidence and progression (estimated RR 0.78; 95% CI 0.63 to 0.97). The available evidence provided less support for a benefit with respect to 4- to 5-year progression of diabetic retinopathy (point estimate was closer to 1 than point estimates for incidence and combined incidence and progression, and the CI overlapped 1; estimated RR 0.88; 95% CI 0.73 to 1.05). The available evidence regarding progression to proliferative diabetic retinopathy or clinically significant macular edema or moderate to severe loss of best-corrected visual acuity did not support a benefit of intervention on blood pressure: estimated RRs and 95% CIs 0.95 (0.83 to 1.09) and 1.06 (0.85 to 1.33), respectively, after 4 to 5 years of follow-up. Findings within subgroups of trial participants (type 1 and type 2 diabetics; participants with normal blood pressure levels at baseline and those with elevated levels) were similar to overall findings.”

“The available evidence supports a beneficial effect of intervention to reduce blood pressure with respect to preventing diabetic retinopathy for up to 4 to 5 years. However, the lack of evidence to support such intervention to slow progression of diabetic retinopathy or to prevent other outcomes considered in this review, along with the relatively modest support for the beneficial effect on incidence, weakens the conclusion regarding an overall benefit of intervening on blood pressure solely to prevent diabetic retinopathy.”

v. Early Atherosclerosis Relates to Urinary Albumin Excretion and Cardiovascular Risk Factors in Adolescents With Type 1 Diabetes: Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT).

“Children with type 1 diabetes are at greatly increased risk for the development of both renal and cardiovascular disease in later life (1,2). Evidence is accumulating that these two complications may have a common pathophysiology, with endothelial dysfunction a key early event.

Microalbuminuria is a recognized marker of endothelial damage (3) and predicts progression to proteinuria and diabetic nephropathy, as well as to atherosclerosis (4) and increased cardiovascular risk (5). It is, however, rare in adolescents with type 1 diabetes who more often have higher urinary albumin excretion rates within the normal range, which are associated with later progression to microalbuminuria and proteinuria (6).”

“The Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT) (10) is designed to examine the impact of minor differences in albumin excretion in adolescents on the initiation and progression of cardiovascular and renal disease. The primary cardiovascular end point in AdDIT is carotid intima-media thickness (cIMT). Subclinical atherosclerosis can be detected noninvasively using high-resolution ultrasound to measure the intima-media thickness (IMT) of the carotid arteries, which predicts cardiovascular morbidity and mortality (11,12). […] The primary aim of this study was to examine the relationship of increased urinary albumin excretion and cardiovascular risk factors in adolescents with type 1 diabetes with structural arterial wall changes. We hypothesized that even minor increases in albumin excretion would be associated with early atherosclerosis but that this would be detectable only in the abdominal aorta. […] A total of 406 adolescents, aged 10–16 years, with type 1 diabetes for more than 1 year, recruited in five centers across Australia, were enrolled in this cross-sectional study”.

“Structural changes in the aorta and carotid arteries could be detected in >50% of adolescents with type 1 diabetes […] The difference in aIMT [aortic intima-media thickness] between type 1 diabetic patients and age- and sex-matched control subjects was equivalent to that seen with a 5- to 6-year age increase in the type 1 diabetic patients. […] Aortic IMT was […] able to better differentiate adolescents with type 1 diabetes from control subjects than was carotid wall changes. Aortic IMT enabled detection of the very early wall changes that are present with even small differences in urinary albumin excretion. This not only supports the concept of early intervention but provides a link between renal and cardiovascular disease.

The independent relationship between aIMT and urinary albumin excretion extends our knowledge of the pathogenesis of cardiovascular and renal disease in type 1 diabetes by showing that the first signs of the development of cardiovascular disease and diabetic nephropathy are related. The concept that microalbuminuria is a marker of a generalized endothelial damage, as well as a marker of renal disease, has been recognized for >20 years (3,20,21). Endothelial dysfunction is the first critical step in the development of atherosclerosis (22). Early rises in urinary albumin excretion precede the development of microalbuminuria and proteinuria (23). It follows that the first structural changes of atherosclerosis could relate to the first biochemical changes of diabetic nephropathy. To our knowledge, this is the first study to provide evidence of this.”

“In conclusion, atherosclerosis is detectable from early adolescence in type 1 diabetes. Its early independent associations are male sex, age, systolic blood pressure, LDL cholesterol, and, importantly, urinary albumin excretion. […] Early rises in urinary albumin excretion during adolescence not only are important for determining risk of progression to microalbuminuria and diabetic nephropathy but also may alert the clinician to increased risk of cardiovascular disease.”

vi. Impact of Islet Autoimmunity on the Progressive β-Cell Functional Decline in Type 2 Diabetes.

“Historically, type 2 diabetes (T2D) has not been considered to be immune mediated. However, many notable discoveries in recent years have provided evidence to support the concept of immune system involvement in T2D pathophysiology (15). Immune cells have been identified in the pancreases of phenotypic T2D patients (35). Moreover, treatment with interleukin-1 receptor agonist improves β-cell function in T2D patients (68). These studies suggest that β-cell damage/destruction mediated by the immune system may be a component of T2D pathophysiology.

Although the β-cell damage and destruction in autoimmune diabetes is most likely T-cell mediated (T), immune markers of autoimmune diabetes have primarily centered on the presence of circulating autoantibodies (Abs) to various islet antigens (915). Abs commonly positive in type 1 diabetes (T1D), especially GAD antibody (GADA) and islet cell Abs (ICA), have been shown to be more common in patients with T2D than in nondiabetic control populations, and the presence of multiple islet Abs, such as GADA, ICA, and tyrosine phosphatase-2 (insulinoma-associated protein 2 [IA-2]), have been demonstrated to be associated with an earlier need for insulin treatment in adult T2D patients (14,1620).”

“In this study, we observed development of islet autoimmunity, measured by islet Abs and islet-specific T-cell responses, in 61% of the phenotypic T2D patients. We also observed a significant association between positive islet-reactive T-cell responses and a more rapid decline in β-cell function as assessed by FCP and glucagon-SCP responses. […] The results of this pilot study led us to hypothesize that islet autoimmunity is present or will develop in a large portion of phenotypic T2D patients and that the development of islet autoimmunity is associated with a more rapid decline in β-cell function. Moreover, the prevalence of islet autoimmunity in most previous studies is grossly underestimated because these studies have not tested for islet-reactive T cells in T2D patients but have based the presence of autoimmunity on antibody testing alone […] The results of this pilot study suggest important changes to our understanding of T2D pathogenesis by demonstrating that the prevalence of islet autoimmune development is not only more prevalent in T2D patients than previously estimated but may also play an important role in β-cell dysfunction in the T2D disease process.”


September 18, 2017 - Posted by | Cancer/oncology, Cardiology, Diabetes, Epidemiology, Immunology, Medicine, Nephrology, Neurology, Ophthalmology, Studies

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