A few diabetes papers of interest

i. Long-Acting C-Peptide and Neuropathy in Type 1 Diabetes: A 12-Month Clinical Trial.

“Lack of C-peptide in type 1 diabetes may be an important contributing factor in the development of microvascular complications. Replacement of native C-peptide has been shown to exert a beneficial influence on peripheral nerve function in type 1 diabetes. The aim of this study was to evaluate the efficacy and safety of a long-acting C-peptide in subjects with type 1 diabetes and mild to moderate peripheral neuropathy. […] C-peptide, an integral component of the insulin biosynthesis, is the 31-amino acid peptide that makes up the connecting segment between the parts of the proinsulin molecule that become the A and B chains of insulin. It is split off from proinsulin and secreted together with insulin in equimolar amounts. Much new information on C-peptide physiology has appeared during the past 20 years […] Studies in animal models of diabetes and early clinical trials in patients with type 1 diabetes (T1DM) demonstrate that C-peptide in physiological replacement doses elicits beneficial effects on early stages of diabetes-induced functional and structural abnormalities of the peripheral nerves, the autonomic nervous system, and the kidneys (9). Even though much is still to be learned about C-peptide and its mechanism of action, the available evidence presents the picture of a bioactive peptide with therapeutic potential.”

“This was a multicenter, phase 2b, randomized, double-blind, placebo-controlled, parallel-group study. The study screened 756 subjects and enrolled 250 at 32 clinical sites in the U.S. (n = 23), Canada (n = 2), and Sweden (n = 7). […] A total of 250 patients with type 1 diabetes and peripheral neuropathy received long-acting (pegylated) C-peptide in weekly dosages […] for 52 weeks. […] Once-weekly subcutaneous administration of long-acting C-peptide for 52 weeks did not improve SNCV [sural nerve conduction velocity], other electrophysiological variables, or mTCNS [modified Toronto Clinical Neuropathy Score] but resulted in marked improvement of VPT [vibration perception threshold] compared with placebo. […] During the course of the 12-month study period, there were no significant changes in fasting blood glucose. Levels of HbA1c remained stable and varied within the treatment groups on average less than 0.1% (0.9 mmol/mol) between baseline and 52 weeks. […] There was a gradual lowering of VPT, indicating improvement in subjects receiving PEG–C-peptide […] after 52 weeks, subjects in the low-dose group had lowered their VPT by an average of 31% compared with baseline; the corresponding value for the high-dose group was 19%. […] The difference in VPT response between the dose groups did not attain statistical significance. In contrast to the SNCV results, VPT in the placebo group changed very little from baseline during the study […] The mTCNS, pain, and sexual function scores did not change significantly during the study nor did subgroup analysis involving the subjects most affected at baseline reveal significant differences between subjects treated with PEG–C-peptide or placebo subjects.”

“Evaluation of the safety population showed that PEG–C-peptide was well tolerated and that there was a low and similar incidence of treatment-related adverse events (11.3–16.4%) in all three treatment groups […] A striking finding in the current study is the observation of a progressive improvement in VPT during the 12-month treatment with PEG–C-peptide […], despite nonsignificant changes in SNCV. This finding may reflect differences in the mechanisms of conduction versus transduction of neural impulses. Changes in transduction reflect membrane receptor characteristics limited to the distal extreme of specific subtypes of sensory axons. In the case of vibration, the principal receptor is Pacinian corpuscles in the skin that are innervated by Aβ fibers. Transduction takes place uniquely at the distal extreme of the axon and is largely influenced by the integrity of this limited segment. Studies have documented that the initial effect of toxic neuropathy is a loss of the surface area of the pseudopod extensions of the distal axon within the Pacinian corpuscle and a consequent diminution of transduction (30). In contrast, changes in the speed of conduction are largely a function of factors that influence the elongated tract of the nerve, including the cross-sectional diameter of axons, the degree of myelination, and the integrity of ion clusters at the nodes of Ranvier (31). Thus, it is reasonable that some aspects of distal sensory function may be influenced by a treatment option that has little or no direct effect on nerve conduction velocity. The alternative is the unsupported belief that any intervention in the onset and progression of a sensory neuropathy must alter conduction velocity.

The marked VPT improvement observed in the current study, although associated with nonsignificant changes in SNCV, other electrophysiological variables, or mTCNS, can be interpreted as targeted improvement in a key aspect of sensory function (e.g., the conversion of mechanical energy to neural signals — transduction). […] Because progressive deficits in sensation are often considered the hallmark of diabetic polyneuropathy, the observed effects of C-peptide in the current study are an important finding.”

ii. Hyperbaric Oxygen Therapy Does Not Reduce Indications for Amputation in Patients With Diabetes With Nonhealing Ulcers of the Lower Limb: A Prospective, Double-Blind, Randomized Controlled Clinical Trial.

“Hyperbaric oxygen therapy (HBOT) is used for the treatment of chronic diabetic foot ulcers (DFUs). The controlled evidence for the efficacy of this treatment is limited. The goal of this study was to assess the efficacy of HBOT in reducing the need for major amputation and improving wound healing in patients with diabetes and chronic DFUs.”

“Patients with diabetes and foot lesions (Wagner grade 2–4) of at least 4 weeks’ duration participated in this study. In addition to comprehensive wound care, participants were randomly assigned to receive 30 daily sessions of 90 min of HBOT (breathing oxygen at 244 kPa) or sham (breathing air at 125 kPa). Patients, physicians, and researchers were blinded to group assignment. At 12 weeks postrandomization, the primary outcome was freedom from meeting the criteria for amputation as assessed by a vascular surgeon. Secondary outcomes were measures of wound healing. […] One hundred fifty-seven patients were assessed for eligibility, with 107 randomly assigned and 103 available for end point adjudication. Criteria for major amputation were met in 13 of 54 patients in the sham group and 11 of 49 in the HBOT group (odds ratio 0.91 [95% CI 0.37, 2.28], P = 0.846). Twelve (22%) patients in the sham group and 10 (20%) in the HBOT group were healed (0.90 [0.35, 2.31], P = 0.823).”

CONCLUSIONS HBOT does not offer an additional advantage to comprehensive wound care in reducing the indication for amputation or facilitating wound healing in patients with chronic DFUs.”

iii. Risk Factors Associated With Severe Hypoglycemia in Older Adults With Type 1 Diabetes.

“Older adults with type 1 diabetes (T1D) are a growing but underevaluated population (14). Of particular concern in this age group is severe hypoglycemia, which, in addition to producing altered mental status and sometimes seizures or loss of consciousness, can be associated with cardiac arrhythmias, falls leading to fractures, and in some cases, death (57). In Medicare beneficiaries with diabetes, hospitalizations related to hypoglycemia are now more frequent than those for hyperglycemia and are associated with high 1-year mortality (6). Emergency department visits due to hypoglycemia also are common (5). […] The T1D Exchange clinic registry reported a remarkably high frequency of severe hypoglycemia resulting in seizure or loss of consciousness in older adults with long-standing T1D (9). One or more such events during the prior year was reported by 1 in 5 of 211 participants ≥65 years of age with ≥40 years’ duration of diabetes (9).”

“Despite the high frequency of severe hypoglycemia in older adults with long-standing T1D, little information is available about the factors associated with its occurrence. We conducted a case-control study in adults ≥60 years of age with T1D of ≥20 years’ duration to assess potential contributory factors for the occurrence of severe hypoglycemia, including cognitive and functional measurements, social support, depression, hypoglycemia unawareness, various aspects of diabetes management, residual insulin secretion (as measured by C-peptide levels), frequency of biochemical hypoglycemia, and glycemic control and variability. […] A case-control study was conducted at 18 diabetes centers in the T1D Exchange Clinic Network. […] Case subjects (n = 101) had at least one severe hypoglycemic event in the prior 12 months. Control subjects (n = 100), frequency-matched to case subjects by age, had no severe hypoglycemia in the prior 3 years.”

RESULTS Glycated hemoglobin (mean 7.8% vs. 7.7%) and CGM-measured mean glucose (175 vs. 175 mg/dL) were similar between case and control subjects. More case than control subjects had hypoglycemia unawareness: only 11% of case subjects compared with 43% of control subjects reported always having symptoms associated with low blood glucose levels (P < 0.001). Case subjects had greater glucose variability than control subjects (P = 0.008) and experienced CGM glucose levels <60 mg/dL for ≥20 min on 46% of days compared with 33% of days in control subjects (P = 0.10). […] When defining high glucose variability as a coefficient of variation greater than the study cohort’s 75th percentile (0.481), 38% of case and 12% of control subjects had high glucose variability (P < 0.001).”

CONCLUSIONS In older adults with long-standing type 1 diabetes, greater hypoglycemia unawareness and glucose variability are associated with an increased risk of severe hypoglycemia.”

iv. Type 1 Diabetes and Polycystic Ovary Syndrome: Systematic Review and Meta-analysis.

“Even though PCOS is mainly an androgen excess disorder, insulin resistance and compensatory endogenous hyperinsulinemia, in close association with obesity and abdominal adiposity, are implicated in the pathogenesis of PCOS in many patients (3,4). In agreement, women with PCOS are at high risk for developing type 2 diabetes and gestational diabetes mellitus (3). […] Type 1 diabetes is a disease produced by an autoimmune injury to the endocrine pancreas that results in the abolition of endogenous insulin secretion. We hypothesized 15 years ago that PCOS could be associated with type 1 diabetes (8). The rationale was that women with type 1 diabetes needed supraphysiological doses of subcutaneous insulin to reach insulin concentrations at the portal level capable of suppressing hepatic glucose secretion, thus leading to exogenous systemic hyperinsulinism. Exogenous hyperinsulinism could then contribute to androgen excess in predisposed women, leading to PCOS as happens in insulin-resistance syndromes.

We subsequently published the first report of the association of PCOS with type 1 diabetes consisting of the finding of a threefold increase in the prevalence of this syndrome compared with that of women from the general population […]. Of note, even though this association was confirmed by all of the studies that addressed the issue thereafter (1016), with prevalences of PCOS as high as 40% in some series (10,16), this syndrome is seldom diagnosed and treated in women with type 1 diabetes.

With the aim of increasing awareness of the frequent association of PCOS with type 1 diabetes, we have conducted a systematic review and meta-analysis of the prevalence of PCOS and associated hyperandrogenic traits in adolescent and adult women with type 1 diabetes. […] Nine primary studies involving 475 adolescent or adult women with type 1 diabetes were included. The prevalences of PCOS and associated traits in women with type 1 diabetes were 24% (95% CI 15–34) for PCOS, 25% (95% CI 17–33) for hyperandrogenemia, 25% (95% CI 16–36) for hirsutism, 24% (95% CI 17–32) for menstrual dysfunction, and 33% (95% CI 24–44) for PCOM. These figures are considerably higher than those reported earlier in the general population without diabetes.”

CONCLUSIONS PCOS and its related traits are frequent findings in women with type 1 diabetes. PCOS may contribute to the subfertility of these women by a mechanism that does not directly depend on glycemic/metabolic control among other negative consequences for their health. Hence, screening for PCOS and androgen excess should be included in current guidelines for the management of type 1 diabetes in women.”

v. Impaired Awareness of Hypoglycemia in Adults With Type 1 Diabetes Is Not Associated With Autonomic Dysfunction or Peripheral Neuropathy.

“Impaired awareness of hypoglycemia (IAH), defined as a diminished ability to perceive the onset of hypoglycemia, is associated with an increased risk of severe hypoglycemia in people with insulin-treated diabetes (13). Elucidation of the pathogenesis of IAH may help to minimize the risk of severe hypoglycemia.

The glycemic thresholds for counterregulatory responses, generation of symptoms, and cognitive impairment are reset at lower levels of blood glucose in people who have developed IAH (4). This cerebral adaptation appears to be induced by recurrent exposure to hypoglycemia, and failure of cerebral autonomic mechanisms may be implicated in the pathogenesis (4). Awareness may be improved by avoidance of hypoglycemia (57), but this is very difficult to achieve and does not restore normal awareness of hypoglycemia (NAH) in all people with IAH. Because the prevalence of IAH in adults with type 1 diabetes increases with progressive disease duration (2,8,9), mechanisms that involve diabetic complications have been suggested to underlie the development of IAH.

Because activation of the autonomic nervous system is a fundamental physiological response to hypoglycemia and provokes many of the symptoms of hypoglycemia, autonomic neuropathy was considered to be a cause of IAH for many years (10). […] Studies of people with type 1 diabetes that have examined the glycemic thresholds for symptom generation in those with and without autonomic neuropathy (13,14,16) have [however] found no differences, and autonomic symptom generation was not delayed. […] The aim of the current study was […] to evaluate a putative association between IAH and the presence of autonomic neuropathy using composite Z (cZ) scores based on a battery of contemporary methods, including heart rate variability during paced breathing, the cardiovascular response to tilting and the Valsalva maneuver, and quantitative light reflex measurements by pupillometry.”

“Sixty-six adults with type 1 diabetes were studied, 33 with IAH and 33 with normal awareness of hypoglycemia (NAH), confirmed by formal testing. Participants were matched for age, sex, and diabetes duration. […] The [study showed] no difference in measures of autonomic function between adults with long-standing type 1 diabetes who had IAH, and carefully matched adults with type 1 diabetes with NAH. In addition, no differences between IAH and NAH participants were found with respect to the NCS [nerve conduction studies], thermal thresholds, and clinical pain or neuropathy scores. Neither autonomic dysfunction nor somatic neuropathy was associated with IAH. We consider that this study provides considerable value and novelty in view of the rigorous methodology that has been used. Potential confounding variables have been controlled for by the use of well-matched groups of participants, validated methods for classification of awareness, a large battery of neurophysiological tests, and a novel statistical approach to provide very high sensitivity for the detection of between-group differences.”

vi. Glucose Variability: Timing, Risk Analysis, and Relationship to Hypoglycemia in Diabetes.

“Glucose control, glucose variability (GV), and risk for hypoglycemia are intimately related, and it is now evident that GV is important in both the physiology and pathophysiology of diabetes. However, its quantitative assessment is complex because blood glucose (BG) fluctuations are characterized by both amplitude and timing. Additional numerical complications arise from the asymmetry of the BG scale. […] Our primary message is that diabetes control is all about optimization and balance between two key markers — frequency of hypoglycemia and HbA1c reflecting average BG and primarily driven by the extent of hyperglycemia. GV is a primary barrier to this optimization […] Thus, it is time to standardize GV measurement and thereby streamline the assessment of its two most important components — amplitude and timing.”

“Although reducing hyperglycemia and targeting HbA1c values of 7% or less result in decreased risk of micro- and macrovascular complications (14), the risk for hypoglycemia increases with tightening glycemic control (5,6). […] Thus, patients with diabetes face a lifelong optimization problem: reducing average glycemic levels and postprandial hyperglycemia while simultaneously avoiding hypoglycemia. A strategy for achieving such an optimization can only be successful if it reduces glucose variability (GV). This is because bringing average glycemia down is only possible if GV is constrained — otherwise blood glucose (BG) fluctuations would inevitably enter the range of hypoglycemia (9).”

“In health, glucose metabolism is tightly controlled by a hormonal network including the gut, liver, pancreas, and brain to ensure stable fasting BG levels and transient postprandial glucose fluctuations. In other words, BG fluctuations in type 1 diabetes result from the activity of a complex metabolic system perturbed by behavioral challenges. The frequency and extent of these challenges and the ability of the person’s system to absorb them determine the stability of glycemic control. The degree of system destabilization depends on each individual’s physiological parameters of glucose–insulin kinetics, including glucose appearance from food, insulin secretion, insulin sensitivity, and counterregulatory response.”

“There is strong evidence that feeding behavior is abnormal in both uncontrolled diabetes and hypoglycemia and that feeding signals within the brain and hormones affecting feeding, such as leptin and ghrelin, are implicated in diabetes (1214). Insulin secretion and action vary with the type and duration of diabetes. In type 1 diabetes, insulin secretion is virtually absent, which destroys the natural insulin–glucagon feedback loop and thereby diminishes the dampening effect of glucagon on hypoglycemia. In addition, insulin is typically administered subcutaneously, which adds delays to insulin action and thereby amplifies the amplitude of glucose fluctuations. […] impaired hypoglycemia counterregulation and increased GV in the hypoglycemic range are particularly relevant to type 1 diabetes: It has been shown that glucagon response is impaired (15), and epinephrine response is typically attenuated as well (16). Antecedent hypoglycemia shifts down BG thresholds for autonomic and cognitive responses, thereby further impairing both the hormonal defenses and the detection of hypoglycemia (17). Studies have established relationships between intensive therapy, hypoglycemia unawareness, and impaired counterregulation (16,1820) and concluded that recurrent hypoglycemia spirals into a “vicious cycle” known as hyperglycemia-associated autonomic failure (HAAF) (21). Our studies showed that increased GV and the extent and frequency of low BG are major contributors to hypoglycemia and that such changes are detectable by frequent BG measurement (2225).”

“The traditional statistical calculation of BG includes standard deviation (SD) (27), coefficient of variation (CV), or other metrics, such as the M-value introduced in 1965 (28), the mean amplitude of glucose excursions (MAGE) introduced in 1970 (29), the glycemic lability index (30), or the mean absolute glucose (MAG) change (31,32). […] the low BG index (LBGI), high BG index (HBGI), and average daily risk range (ADRR) […] are [all] based on a transformation of the BG measurement scale […], which aims to correct the substantial asymmetry of the BG measurement scale. Numerically, the hypoglycemic range (BG <70 mg/dL) is much narrower than that in the hyperglycemic range (BG >180 mg/dL) (34). As a result, whereas SD, CV, MAGE, and MAG are inherently biased toward hyperglycemia and have a relatively weak association with hypoglycemia, the LBGI and ADRR account well for the risk of hypoglycemic excursions. […] The analytical form of the scale transformation […] was based on accepted clinical assumptions, not on a particular data set, and was fixed 17 years ago, which made the approach extendable to any data set (34). On the basis of this transformation, we have developed our theory of risk analysis of BG data (35), defining a computational risk space that proved to be very suitable for quantifying the extent and frequency of glucose excursions. The utility of the risk analysis has been repeatedly confirmed (9,25,3638). We first introduced the LBGI and HBGI, which were specifically designed to be sensitive only to the low and high end of the BG scale, respectively, accounting for hypo- and hyperglycemia without overlap (24). Then in 2006, we introduced the ADRR, a measure of GV that is equally sensitive to hypo- and hyperglycemic excursions and is predictive of extreme BG fluctuations (38). Most recently, corrections were introduced that allowed the LBGI and HBGI to be computed from CGM data with results directly comparable to SMBG [self-monitoring of BG] (39).”

“[A]lthough GV has richer information content than just average glucose (HbA1c), its quantitative assessment is not straightforward because glucose fluctuations carry two components: amplitude and timing.

The standard assessment of GV is measuring amplitude. However, when measuring amplitude we should be mindful that deviations toward hypoglycemia are not equal to deviations toward hyperglycemia—a 20 mg/dL decline in BG levels from 70 to 50 mg/dL is clinically more important than a 20 mg/dL raise of BG from 160 to 180 mg/dL. We explained how to fix that with a well-established rescaling of the BG axis introduced more than 15 years ago (34). […] In addition, we should be mindful of the timing of BG fluctuations. There are a number of measures assessing GV amplitude from routine SMBG, but the timing of readings is frequently ignored even if the information is available (42). Yet, contrary to widespread belief, BG fluctuations are a process in time and the speed of transition from one BG state to another is of clinical importance. With the availability of CGM, the assessment of GV timing became not only possible but also required (32). Responding to this necessity, we should keep in mind that the assessment of temporal characteristics of GV benefits from mathematical computations that go beyond basic arithmetic. Thus, some assistance from the theory and practice of time series and dynamical systems analysis would be helpful. Fortunately, these fields are highly developed, theoretically and computationally, and have been used for decades in other areas of science […] The computational methods are standardized and available in a number of software products and should be used for the assessment of GV. […] There is no doubt that the timing of glucose fluctuations is clinically important, but there is a price to pay for its accurate assessment—a bit higher level of mathematical complexity. This, however, should not be a deterrent.”

vii. Predictors of Increased Carotid Intima-Media Thickness in Youth With Type 1 Diabetes: The SEARCH CVD Study.

“Adults with childhood-onset type 1 diabetes are at increased risk for premature cardiovascular disease (CVD) morbidity and mortality compared with the general population (1). The antecedents of CVD begin in childhood (2), and early or preclinical atherosclerosis can be detected as intima-media thickening in the artery wall (3). Carotid intima-media thickness (IMT) is an established marker of atherosclerosis because of its associations with CVD risk factors (4,5) and CVD outcomes, such as myocardial infarction and stroke in adults (6,7).

Prior work […] has shown that youth with type 1 diabetes have higher carotid IMT than control subjects (813). In cross-sectional studies, risk factors associated with higher carotid IMT include younger age at diabetes onset, male sex, adiposity, higher blood pressure (BP) and hemoglobin A1c (HbA1c), and lower vitamin C levels (8,9,11). Only one study has evaluated CVD risk factors longitudinally and the association with carotid IMT progression in youth with type 1 diabetes (14). In a German cohort of 70 youth with type 1 diabetes, Dalla Pozza et al. (14) demonstrated that CVD risk factors, including BMI z score (BMIz), systolic BP, and HbA1c, worsened over time. They also found that baseline HbA1c and baseline and follow-up systolic BP were significant predictors of change in carotid IMT over 4 years.”

“Before the current study, no published reports had assessed the impact of changes in CVD risk factors and carotid IMT in U.S. adolescents with type 1 diabetes. […] Participants in this study were enrolled in SEARCH CVD, an ancillary study to the SEARCH for Diabetes in Youth that was conducted in two of the five SEARCH centers (Colorado and Ohio). […] This report includes 298 youth who completed both baseline and follow-up SEARCH CVD visits […] At the initial visit, youth with type 1 diabetes were a mean age of 13.3 ± 2.9 years (range 7.6–21.3 years) and had an average disease duration of 3.6 ± 3.3 years. […] Follow-up data were obtained at a mean age of 19.2 ± 2.7 years, when the average duration of type 1 diabetes was 10.1 ± 3.9 years. […] In the current study, we show that older age (at baseline) and male sex were significantly associated with follow-up IMT. By using AUC measurements, we also show that a higher BMIz exposure over ∼5 years was significantly associated with IMT at follow-up. From baseline to follow-up, the mean BMI increased from within normal limits (21.1 ± 4.3 kg/m2) to overweight (25.1 ± 4.8 kg/m2), defined as a BMI ≥25 kg/m2 in adults (26,27). This large change in BMI may explain why BMIz was the only modifiable risk factor to be associated with follow-up IMT in the final models. Whether the observed increase in BMIz over time is part of the natural evolution of diabetes, aging in an obesogenic society, or a consequence of intensive insulin therapy is not known.”

“Data from the DCCT/EDIC cohorts have suggested nontraditional risk factors, including acute phase reactants, thrombolytic factors, cytokines/adipokines (34), oxidized LDL, and advanced glycation end products (30) may be important biomarkers of increased CVD risk in adults with type 1 diabetes. However, many of these nontraditional risk factors […] were not found to associate with IMT until 8–12 years after the DCCT ended, at the time when traditional CVD risk factors were also found to predict IMT. Collectively, these findings suggest that many traditional and nontraditional risk factors are not identified as relevant until later in the atherosclerotic process and highlight the critical need to better identify risk factors that may influence carotid IMT early in the course of type 1 diabetes because these may be important modifiable CVD risk factors of focus in the adolescent population. […] Although BMIz was the only identified risk factor to predict follow-up IMT at this age [in our study], it is possible that increases in dyslipidemia, BP, smoking, and HbA1c are related to carotid IMT but only after longer duration of exposure.”


July 13, 2017 - Posted by | Cardiology, Diabetes, Medicine, Neurology, Studies

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