Metformin: Effects on Micro and Macrovascular Complications in Type 2 Diabetes

INTRODUCTION: The antihyperglycaemic agent metformin is widely used in the treatment of type 2 diabetes. Data from the UK Prospective Diabetes Study and retrospective analyses of large healthcare databases concur that metformin reduces the incidence of myocardial infarction and increases survival in these patients. This apparently vasoprotective effect appears to be independent of the blood glucose-lowering efficacy. EFFECTS OF METFORMIN: Metformin has long been known to reduce the development of atherosclerotic lesions in animal models, and clinical studies have shown the drug to reduce surrogate measures such as carotid intima-media thickness. The anti-atherogenic effects of metformin include reductions in insulin resistance, hyperinsulinaemia and obesity. There may be modest favourable effects against dyslipidaemia, reductions in pro-inflammatory cytokines and monocyte adhesion molecules, and improved glycation status, benefiting endothelial function in the macro- and micro-vasculature. Additionally metformin exerts anti-thrombotic effects, contributing to overall reductions in athero-thrombotic risk in type 2 diabetic patients.     

Autonomic Neuropathy in Type I Diabetes: Influence of Duration and Other Diabetic Complications

ABSTRACT To evaluate the influence of duration on the development of autonomic neuropathy (AN) a group of type I diabetic patients (n=58) who had been diagnosed between the ages of 15 and 25 years was investigated. The duration of diabetes varied from 2 months to 30 years (mean 13 years). AN tests included a deep breathing test (E/I ratio) and an orthostatic test on tilt table (acceleration and brake indices) and the results were corrected for age. A clear correlation between AN test and duration of diabetes was shown only for the En ratio (r= -0.44, p<0.001). On the other hand, deteriorations in the brake index were unrelated to the duration of diabetes and occurred early; 35% of the patients with a duration of 10 years or less showed an abnormal brake index. Autonomic test deviations were related to other diabetic complications. The En ratio and the acceleration index were especially low in patients with retinopathy as well as in patients with symptoms of AN if combined with peripheral neuropathy (PN). The brake index was low in patients with symptoms of AN independent of PN.     

Relationship between Pancreas Exocrine Insufficiency and Cardiac Autonomic Neuropathy in Patients with Type 2 Diabetes Mellitus

BackgroundThe exocrine function of the pancreas is controlled by the autonomic nervous system (ANS), and autonomic neuropathy is a common and serious complication of diabetes. There are many factors contributing to the development of autonomic neuropathy in diabetic patients. Cardiovascular tests have been developed to evaluate the function of the ANS. This study investigated the relationship between cardiovascular autonomic neuropathy (CAN) and pancreas exocrine insufficiency (PEI) in diabetic patients.Methods This study evaluated 110 individuals with type 2 diabetes mellitus (T2DM) and 40 healthy volunteers. Autonomous neuropathy tests were utilized to diagnose patients, and Ewing and Clarke’s criteria were employed to assess the severity of autonomous dysfunction. Stool samples were also collected from patients to measure fecal elastase-1 (FE-1). Results A 65.5% incidence of PEI was observed in DM patients. There was no significant correlation among the duration of disease, C-peptide, HbA1c, and PEI, respectively (P = .782, P = .521, P = .580). However, a significant difference between DM patients and controls in terms of cardiac dysautonomia (P = .001) was seen. Moreover, a statistically significant correlation between the degree of cardiac dysautonomia and FE-1 level was observed within the patient group (P =.001).Conclusion It is possible that the disruption of exocrine hormone secretion in the pancreas due to the impairment of enteropancreatic reflexes is secondary to diabetic autonomic neuropathy and resulting in PEI. This study also showed that autonomic neuropathy might develop and cause PEI in diabetic patients without known added confounding factors.     

Autonomic neuropathy in Type 2 diabetic patients is associated with hyperinsulinaemia and hypertriglyceridaemia.

AIMS: To clarify whether parasympathetic neuropathy in Type 2 diabetic patients is associated with features of the insulin resistance syndrome. METHODS: Blood pressures, glycaemic control (HbA1c), plasma lipids, residual beta-cell function (fasting plasma C-peptide), autonomic nerve function, urinary albumin excretion and glomerular filtration rate (Cr-EDTA clearance) were evaluated in 82 Type 2 diabetic patients (age 63+/-years) 5 years after diagnosis of diabetes. RESULTS: Parasympathetic neuropathy (an abnormal age corrected E/I ratio) was found in 24/82 (29%) patients. After adjustment for body mass index (BMI), patients with parasympathetic neuropathy had elevated fasting plasma C-peptide (P < 0.001) and triglyceride (Tg) (P < 0.05) levels compared with patients without parasympathetic neuropathy. In addition, the age corrected E/I ratio correlated inversely with Tg (r=-0.31; P<0.01) and fasting plasma C-peptide (r=-0.32; P < 0.01) in the Type 2 diabetic patients. CONCLUSION: Autonomic neuropathy 5 years after diagnosis of Type 2 diabetes is associated with an unfavourable metabolic risk profile.     

A Novel Quantitative Method for Diabetic Cardiac Autonomic Neuropathy Assessment in Type 1 Diabetic Mice

In this work, we used a sensitive and noninvasive computational method to assess diabetic cardiovascular autonomic neuropathy (DCAN) from pulse oximeter (photoplethysmographic; PPG) recordings from mice. The method, which could be easily applied to humans, is based on principal dynamic mode (PDM) analysis of heart rate variability (HRV). Unlike the power spectral density, PDM has been shown to be able to separately identify the activities of the parasympathetic and sympathetic nervous systems without pharmacological intervention. HRV parameters were measured by processing PPG signals from conscious 1.5- to 5-month-old C57/BL6 control mice and in Akita mice, a model of insulin-dependent type 1 diabetes, and compared with the gold-standard Western blot and immunohistochemical analyses. The PDM results indicate significant cardiac autonomic impairment in the diabetic mice in comparison to the controls. When tail-cuff PPG recordings were collected and analyzed starting from 1.5 months of age in both C57/Bl6 controls and Akita mice, onset of DCAN was seen at 3 months in the Akita mice, which persisted up to the termination of the recording at 5 months. Western blot and immunohistochemical analyses also showed a reduction in nerve density in Akita mice at 3 and 4 months as compared to the control mice, thus, corroborating our PDM data analysis of HRV records. Western blot analysis of autonomic nerve proteins corroborated the PPG-based HRV analysis via the PDM approach. In contrast, traditional HRV analysis (based on either the power spectral density or time-domain measures) failed to detect the nerve rarefaction.     

Cardiovascular Risk Factors Increase the Risks of Diabetic Peripheral Neuropathy in Patients With Type 2 Diabetes Mellitus: The Taiwan Diabetes Study

This study aimed to examine whether poor glycemic control, measured by glycated hemoglobin A1C (HbA1c) and other cardiovascular risk factors, can predict diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes mellitus (DM).Patients aged ≥30 years with type 2 DM, enrolled in the National Diabetes Care Management Program, and free of DPN (n = 37,375) in the period 2002 to 2004 were included and followed up until 2011. The related factors were analyzed using Cox proportional hazards regression models.For an average follow-up of 7.00 years, 8379 cases of DPN were identified, with a crude incidence rate of 32.04/1000 person-years. After multivariate adjustment, patients with HbA1c levels 7 to 8%, 8 to 9%, 9 to 10%, and ≥10% exhibited higher risk of DPN (adjusted HR: 1.11 [1.04–1.20], 1.30 [1.21–1.40], 1.32 [1.22–1.43], and 1.62 [1.51–1.74], respectively) compared with patients with HbA1c level 6 to 7%. There was a significant linear trend in DPN incidence with increasing HbA1c (P < 0.001) and significant HRs of DPN for patients with HbA1c level ≥7%, blood pressure ≥130/85 mm Hg, triglycerides (TG) ≥150 mg/dL, high density of lipoprotein-cholesterol (HDL-C) <40 mg/dL in males and <50 mg/dL in females, low density of lipoprotein-cholesterol (LDL-C) ≥100 mg/dL, and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m².Patients with type 2 DM and HbA1c ≥7.0% exhibit increased risk of DPN, demonstrating a linear relationship. The incidence of DPN is also associated with poor glucose control and cardiovascular risk factors like hypertension, hyper-triglyceridemia, low HDL-C, high LDL-C, and decreased eGFR.     

Prevalence and Risk Factors for Aspirin Resistance in Elderly Patients With Type 2 Diabetes

Background

Aspirin resistance in patients with diabetes is recognized. However, the prevalence and related risk factors for aspirin resistance in elderly patients with Type 2 diabetes have not been reported, which is why we undertook this study.

Methods

One hundred and forty elderly patients (age, 73.84 ± 8.02 years) with Type 2 diabetes receiving daily aspirin therapy (≥75 mg) over 1 month were recruited. Platelet aggregation was measured by light transmission aggregometry (LTA) and thrombelastography (TEG) platelet mapping assay. The definitions of aspirin resistance were 20% or greater arachidonic acid-induced and 70% or greater adenosine diphosphate-induced aggregation by LTA. Aspirin semiresponders were defined as meeting one (but not both) of these criteria. Aspirin resistance by TEG was defined as 50% or greater aggregation induced by arachidonic acid.

Results

By LTA, 6 (4.3%) patients with Type 2 diabetes were found to be resistant to aspirin therapy; 44 (31.4%) patients were semiresponders. By TEG, 31 patients (22.1%) were aspirin resistant. Of the 31 patients who were aspirin-resistant by TEG, 3 were aspirin-resistant by LTA. Eight of 44 semiresponders by LTA were aspirin-resistant by TEG. In the multivariate logistic regression analysis, being female (odds ratio: 5.54, 95% confidence interval: 1.17–27.47, p = 0.036) and homocysteine levels (odds ratio: 1.15, 95% confidence interval: 1.00–1.31, p = 0.043) were significant risk factors for aspirin resistance by TEG.

Conclusion

The prevalence of aspirin resistance in elderly patients with Type 2 diabetes was considerably higher in female patients and in patients with higher serum levels of homocysteine.     

Risk Factors for Type 2 Diabetes Among Women with Gestational Diabetes: A Systematic Review

We conducted a systematic review of studies examining risk factors for the development of type 2 diabetes among women with previous gestational diabetes. Our search strategy yielded 14 articles that evaluated 9 categories of risk factors of type 2 diabetes in women with gestational diabetes: anthropometry, pregnancy-related factors, postpartum factors, parity, family history of type 2 diabetes, maternal lifestyle factors, sociodemographics, oral contraceptive use, and physiologic factors. The studies provided evidence that the risk of type 2 diabetes was significantly higher in women having increased anthropometric characteristics with relative measures of association ranging from 0.8 to 8.7 and women who used insulin during pregnancy with relative measures of association ranging between 2.8 and 4.7. A later gestational age at diagnosis of gestational diabetes, >24 weeks gestation on average, was associated with a reduction in risk of development of type 2 diabetes with relative measures of association ranging between 0.35 and 0.99. We concluded that there is substantial evidence for 3 risk factors associated with the risk of type 2 diabetes in women having gestational diabetes.     

Cardiovascular autonomic dysfunction predicts acute ischaemic stroke in patients with Type 2 diabetes mellitus: a 7‐year follow‐up study

Aims We investigated whether cardiovascular autonomic neuropathy (CAN) is associated with acute ischaemic stroke in patients with Type 2 diabetes. Methods From 1999 to 2000, cardiovascular autonomic function tests were conducted in patients with Type 2 diabetes (n = 1458). Patients were followed up between 2006 and 2007. Standard tests for CAN measured heart rate variability parameters [expiration‐to‐inspiration (E/I) ratio, responses to the Valsalva manoeuvre and standing]. Using the American Diabetes Association criteria, the CAN scores were determined from the results of each test as follows: 0 = normal, 1 = abnormal (total maximum score 3). We assessed the development of acute ischaemic stroke events. Results The prevalence of CAN at baseline was 55.7% (E/I 17.1%, Valsalva 39.4%, posture 27.3%) (n = 1126). During follow‐up, 131 patients (11.6%) developed acute ischaemic stroke. The vascular events were more frequent in older patients (P < 0.001) and in those with diabetes of longer duration (P = 0.022), hypertension (P < 0.001) or diabetic retinopathy (P = 0.03) than in patients without vascular events. Patients with ischaemic stroke had higher creatinine levels (P = 0.045) and higher urine albumin excretion (P = 0.025) than those of patients without stroke. Cox proportional hazard regression analysis revealed that the CAN score was associated with the development of acute ischaemic stroke (total score 0 vs. 3, adjusted hazard ratio 2.7, 95% CI 1.3–5.5, P = 0.006). Conclusion Cardiovascular autonomic dysfunction was significantly associated with the development of ischaemic stroke in patients with Type 2 diabetes.     

Constipation Is a Frequent Problem Associated with Vascular Complications in Patients with Type 2 Diabetes: A Cross-sectional Study

Objective Diabetes is recognized as an underlying disease of constipation. However, the prevalence of constipation varies according to the diagnostic criteria applied. We investigated the prevalence of constipation based on the new guideline for constipation in Japanese patients with type 2 diabetes and examined the relationship with the clinical background, including diabetic vascular complications. Methods Questionnaire surveys including items concerning the diagnosis and treatment status of constipation were administered to 410 patients with type 2 diabetes. Results Although 29% of the patients considered that they had experienced constipation (self-judged), only 14% had consulted a physician about constipation. The prevalence of chronic constipation based on the guideline was 26%. After including laxative users, constipation was finally found in 36%. Despite the use of laxatives (n=81), 51% of the patients were still diagnosed with chronic constipation. Patients with constipation (chronic constipation or laxative use) were significantly older and had a longer duration of diabetes than those without constipation. The body mass index (BMI) of patients with constipation (24.9±3.8 kg/m²) was significantly lower than that of those without constipation (26.3±4.6 kg/m²). Diabetic neuropathy (49% vs. 32%) and coronary heart disease (CHD) (27% vs. 13%) were significantly more frequent in the patients with constipation than in those without constipation. A multivariate logistic regression analysis revealed that gender, BMI, diabetic neuropathy, insulin use, and CHD were significantly associated with constipation. Conclusion An accurate diagnosis of constipation is desirable in patients with type 2 diabetes because constipation is independently associated with CHD.     

2型糖尿病患者慢性并发症的患病率及相关因素分析

<正>糖尿病是一组呈全球流行趋势的慢性代谢性疾病。随着经济的发展和人民生活方式的改变以及人口老龄化,糖尿病患病率逐年增加是全球范围内的共同趋势。美国国家糖尿病委员会报道糖尿病病人患     

Effects of Exenatide on Diabetes, Obesity, Cardiovascular Risk Factors, and Hepatic Biomarkers in Patients with Type 2 Diabetes

Obesity increases the risk of diabetes up to 90-fold and worsens hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease. For patients with type 2 diabetes, weight loss can trigger improvements in all these conditions and decrease the need for glucose-lowering agents. The incretin mimetic exenatide shares many glucoregulatory properties with native glucagon-like peptide-1, including enhancement of glucose-dependent insulin secretion, glucose-dependent suppression of inappropriately high glucagon secretion, slowing of gastric emptying, and reduction of food intake in patients with type 2 diabetes. Exenatide treatment was associated with progressive weight loss in the majority of patients in clinical trials. In addition, patients with elevated markers of liver injury at baseline showed improvements. Therefore, exenatide represents a unique option for adjunctive therapy for patients with type 2 diabetes not achieving adequate glycemic control on oral antidiabetic agents, especially in patients for whom weight gain would be an additional contraindication.     

Are Conventional Risk Factors for Mortality Relevant in Type 2 Diabetes?

One-hundred and ninety-one men with Type 2 (non-insulin-dependent) diabetes mellitus, participants in the Whitehall Survey, were followed for 15 years. Age-adjusted all-cause and ischaemic heart disease (IHD) mortality rates were significantly increased in the diabetic men. Of four putative risk factors for IHD ascertained in the survey (plasma cholesterol, systolic blood pressure, cigarette smoking, body mass index) only blood pressure was a significant predictor in univariate Cox regression analysis. A review of comparable studies revealed lack of consistency in the association of these risk factors (derived from studies in non-diabetic populations) and mortality in individuals with Type 2 diabetes. Given the absence of clinical trial data, risk factor intervention in Type 2 diabetes is currently based upon inference derived from studies in non-diabetic subjects.     

Risk Factors for Early Failure of Arteriovenous Vascular Access Among Patients With Type 2 Diabetes Mellitus

The aim of the study was to identify the potential risk factors for early arteriovenous access failure in a diabetic population. The data of 223 end‐stage renal disease (ESRD) patients with type 2 diabetes who had an arteriovenous fistula (AVF) or arteriovenous graft (AVG) placed as their initial vascular accesses were retrospectively reviewed. The association between clinical factors and risk for early failure was then analyzed. In multivariate analysis, the predictors associated with early failure were female gender (odds ratio (95% confidence interval): 2.52 (1.32–4.81); P = 0.005), AVF with prior peritoneal dialysis (3.26 (1.05‐10.11); P = 0.039), and lower hemoglobin level (P = 0.015). The results of significant predictors in the AVF group remained similar to the entire study population. In conclusion, there was an association of female gender, AVF with prior peritoneal dialysis and lower hemoglobin level with early arteriovenous access failure in a diabetic ESRD population.     

Executive Functioning in Older Adult Outpatients With Type 2 Diabetes Mellitus: A Preliminary Study

Given the multi-componential nature of executive functions, we compared 48 outpatients affected by Type 2 diabetes and 49 control subjects on the executive domains of inhibition, updating, shifting, and word fluency. Variables commonly associated with diabetes were considered in explaining the relationship between diabetes and executive functioning. Each participant underwent a clinical and cognitive (addressing the four executive domains) evaluation. Raw test scores were standardized per domain and compared between groups. Possible risk factors related to diabetes were examined. The diabetes group scored lower than the control subjects only in the inhibition measure, whereas no differences resulted in the other executive domains.     

The Toxic Effects of Serum from Patients with Type 1 Diabetes Mellitus on Mouse Neuroblastoma Cells: A New Mechanism for Development of Diabetic Autonomic Neuropathy

The pathogenesis of diabetic neuropathy is incompletely understood. The possibility that humoral neurotoxic factors contribute as a cause of diabetic neuropathy was tested by application of serum from patients with Type 1 and Type 2 diabetes to mouse neuroblastoma cells, which have the characteristics of adrenergic neurons in culture. Serum from patients with Type 1 diabetes and somatic neuropathy significantly inhibited both proliferation and differentiation of neuroblastoma cells, while serum from patients with Type 1 diabetes but no symptoms of neuropathy and patients with Type 2 diabetes and neuropathy had no effect on proliferation, and serum from Type 2 patients only marginally inhibited differentiation. The effects of Type 1 diabetic serum could be reversed by pre-absorption of the serum to neuroblastoma cells, and were independent of glucose levels. Immunoglobulins precipitated from the sera mimicked the effects of whole sera. These results suggest that Type 1 diabetes mellitus causes a change in serum composition, possibly related to autoimmunity, that is capable of contributing to adrenergic autonomic neuropathy in diabetic patients.