Akira Kuroe

Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus.

The aim of the present study was to investigate the association of serum adiponectin concentration with regional adiposity and insulin resistance in subjects with type 2 diabetes mellitus. A total of 73 Japanese men with type 2 diabetes (aged 59 +/- 11 years and body mass index [BMI] 23.8 +/- 3.0 kg/m(2), mean +/- SD) were studied. Fasting serum adiponectin and leptin concentrations were determined by radioimmunoassay. Regional adiposity was measured by abdominal computed tomography (CT) at the umbilical level, and insulin resistance was estimated by homeostasis model assessment (HOMA-R). Univariate regression analysis showed that serum adiponectin levels were negatively correlated with subcutaneous and visceral fat areas. With multivariate regression analysis, visceral fat area was a predominant determinant of serum adiponectin levels. In contrast, subcutaneous fat area was strongly associated with serum leptin concentrations. Among subcutaneous and visceral fat areas, BMI, and serum leptin levels, both subcutaneous and visceral fat areas were independently associated with HOMA-R. In another model incorporating serum adiponectin levels, serum adiponectin levels were selected as an independent determinant of HOMA-R instead of visceral fat area. In conclusion, hypoadiponectinemia was associated with visceral fat accumulation rather than subcutaneous fat depot in Japanese men with type 2 diabetes mellitus. Both subcutaneous and visceral fat accumulation contribute to insulin resistance in these subjects, and the contribution of visceral fat may be mediated, in part, by hypoadiponectinemia.

Antioxidant α-tocopherol ameliorates glycemic control of GK rats, a model of type 2 diabetes

We have shown recently that oxidative stress by chronic hyperglycemia damages the pancreatic β‐cells of GK rats, a model of non‐obese type 2 diabetes, which may worsen diabetic condition and suggested the administration of antioxidants as a supportive therapy. To determine if natural antioxidant α‐tocopherol (vitamin E) has beneficial effects on the glycemic control of type 2 diabetes, GK rats were fed a diet containing 0, 20 or 500 mg/kg diet α‐tocopherol. Intraperitoneal glucose tolerance test revealed a significant increment of insulin secretion at 30 min and a significant decrement of blood glucose levels at 30 and 120 min after glucose loading in the GK rats fed with high α‐tocopherol diet. The levels of glycated hemoglobin A1c, an indicator of glycemic control, were also reduced. Vitamin E supplementation clearly ameliorated diabetic control of GK rats, suggesting the importance of not only dietary supplementation of natural antioxidants but also other antioxidative intervention as a supportive therapy of type 2 diabetic patients.

Impaired β-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance

The development of type 2 diabetes mellitus is characterized by both impaired beta-cell function and increasing insulin resistance. To clarify the roles of them in developing type 2 diabetes, we evaluated insulin resistance by HOMA-IR and insulin secretion by HOMA beta-cell in 453 Japanese subjects whose fasting plasma glucose (FPG) and HbA(1c) levels were within normal range. HOMA beta-cell was found to decrease in the over 30 years groups, while HOMA-IR increased with body mass index (BMI). To analyze the reserve capacity of insulin secretion and insulin sensitivity, the 67 of them, who underwent a standard oral glucose tolerance test and were diagnosed with normal glucose tolerance (NGT), were divided into four degrees of BMI age-adjusted to 50 years. They were compared for insulinogenic index and ISI composite proposed by Matsuda and DeFronzo across the range of BMI. ISI composite was significantly less in the highest BMI group, while insulin secretion did not increase in the higher BMI groups. The subjects with higher BMI had remarkably lower insulinogenic indices than those with lower BMI. These data suggest that insulin secretory reserve is insufficient to compensate for increased insulin resistance in Japanese people with NGT at about 50 years of age.

Little enhancement of meal-induced glucagon-like peptide 1 secretion in Japanese: Comparison of type 2 diabetes patients and healthy controls

Although glucose‐dependent insulinotropic polypeptide (GIP) levels have been characterized previously, GLP‐1 levels in Asians remain unclear. Here, we investigate total and intact levels of GLP‐1, as well as GIP during oral glucose and meal tolerance tests (OGTT and MTT) in Japanese patients with or without type 2 diabetes (T2DM). Seventeen Japanese healthy controls and 18 age‐matched and untreated patients with T2DM of short duration participated in the present study. Fasting levels of total GPL‐1 were similar between the two groups (approximately 15 pM), and intact GLP‐1 levels were considerably low in both groups (less than 1 pM). In both groups, total GLP‐1 reached a peak 30 min after glucose ingestion (30–40 pM), whereas intact GLP‐1 levels remained low with no significant peak. In MTT, total and intact GLP‐1 showed no obvious peak. The current data indicate that intact GLP‐1 levels are considerably low in the Japanese and that meal‐induced enhancement of GLP‐1 secretion is negligible in the Japanese. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00010.x, 2010)

Genomic variation in pancreatic ion channel genes in Japanese type 2 diabetic patients.

Many genetic diseases are caused by mutations in ion channel genes. Because type 2 diabetes is characterized by pancreatic β‐cell insensitivity to glucose, the genes responsible for glucose metabolism and calcium signaling in pancreatic β‐cells are candidate type 2 diabetes susceptibility genes.

Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients

AIMS Hypersecretion of glucagon and reduced insulin secretion both contribute to hyperglycemia in type 2 diabetes (T2DM). However, the relative contributions of impaired glucagon and insulin secretions in glucose excursions at the various stages of T2DM development remain to be determined. METHODS The responses of glucagon and insulin as well as those of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) were examined before and after ingestion of glucose or mixed meal in Japanese subjects with normal or impaired glucose tolerance (NGT and IGT) and in non-obese, untreated T2DM of short duration. RESULTS In OGTT, T2DM showed a rise in glucagon at 0-30 min, unlike NGT and IGT, along with reduced insulin. In MTT, all three groups showed a rise in glucagon at 0-30 min, with that in T2DM being highest, while T2DM showed a significant reduction in insulin. Linear regression analyses revealed that glucose area under the curve (AUC)0-120 min was associated with glucagon-AUC0-30 min and insulin-AUC0-30 min in both OGTT and MTT. Total and biologically intact GIP and GLP-1 levels were similar among the three groups. CONCLUSIONS Disordered early phase insulin and glucagon secretions but not incretin secretion are involved in hyperglycemia after ingestion of nutrients in T2DM of even a short duration.

Factors influencing the durability of the glucose-lowering effect of sitagliptin combined with a sulfonylurea.

We analyzed the changes of glycemic control over 12 months and the factors influencing blood glucose in 162 Japanese patients with type 2 diabetes having inadequate glycemic control despite sulfonylurea‐based therapy who received add‐on sitagliptin. Hemoglobin A1c (HbA1c) decreased significantly after 4 weeks of treatment, and this improvement was maintained for 1 year, although HbA1c was slightly higher in week 52 than in week 24. Comparison of the patients showing a ≥0.4% increase of HbA1c between weeks 24 and 52 (n = 57) with the others (n = 105) showed a significant difference in the change of bodyweight, as well as the dose of glibenclamide (both P < 0.01). Although combined therapy with sitagliptin and a sulfonylurea seems to be effective for at least 1 year, blood glucose levels are more likely to increase again in patients who show greater weight gain after 24 weeks of treatment and those receiving a higher dose of glibenclamide.

The role of the TSC-22 ( /396) A/G variant in the development of diabetic nephropathy

TSC-22 is a leucine zipper transcriptional factor and expression of the TSC-22 gene is highly induced by TGF-beta treatment. We estimated the frequency of the -396 A/G polymorphism of the TSC-22 gene with an Alu I-Restriction fragment length polymorphism (RFLP) method in 498 Japanese subjects with type 2 diabetes mellitus. We also determined the promoter activity. The diabetic patients with the AA genotype had a significantly higher incidence of the diabetic nephropathy (vs. the AG genotype, P<0.05, odds ratio: 1.95; 95% confidence intervals 1.14-3.33). There was no significant difference in the promoter activity between the fragments with -396A and -396G. These findings suggest that the TSC-22 gene (-396) A allele is associated with an increasing risk of the diabetic nephropathy.

Short-term intensive glycemic control improves vibratory sensation in type 2 diabetes

Strict long-term glycemic control has been reported to prevent or improve diabetic peripheral neuropathy, but the effects of short-term glycemic control have not been clarified in patients with type 2 diabetes. To investigate reversibility of impaired vibratory sensation by short-term glycemic control, we used the TM31 liminometer and C64 tuning fork methods to measure peripheral neuropathy. Thirty-one type 2 diabetes patients with poor glycemic control (HbA1c: 10.8+/-0.4%, mean+/-S.E.M., range from 7.9% to 16.2%) were administered strict glycemic control. Vibratory sensation before and after short-term glycemic control was evaluated, and the metabolic profile including plasma glucose, HbA1c, total cholesterol, HDL cholesterol, triglyceride, and free fatty acid (FFA) was measured. After 20.0+/-2.1 days of strict glycemic control, vibratory sensation improved significantly in both upper and lower extremities, assessed by TM31 liminometer and C64 tuning fork. Along with the improved glycemic control, lipid metabolism (total cholesterol, triglyceride and FFA) was significantly improved. Thus, short-term intensive glycemic control can improve vibratory sensation, metabolic changes in glucose and lipid metabolism being the factors responsible for improved of peripheral nerve function.

Soluble Tumor Necrosis Factor Receptor 2 Is Independently Associated With Brachial-Ankle Pulse-Wave Velocity in Nonobese Japanese Type 2 Diabetic Patients

Type 2 diabetes is associated with high mortality and morbidity due to atherosclerosis. Biermen (1) estimated that typical risk factors, including blood pressure, cholesterol, and smoking, can account for no more than 30% of excess cardiovascular risk factor in diabetic patients. Thus, other factors seem to play a role in the progression of atherosclerosis in diabetes. Aortic stiffness measured by pulse- wave velocity (PWV) is shown to be highly predictive of cardiovascular mortality in type 2 diabetic patients (2). While age and blood pressure are shown …