Common uncoupling protein 2 (UCP2) promoter polymorphism ؊866G/A is reported to be associated with its expression in adipose tissue and the risk of obesity in Caucasians. On the other hand, several studies suggested that UCP2 expression in ␤-cells is an important determinant of insulin secretion. In the Japanese population, morbid obesity is very rare, and insulin secretion capacity is relatively low as compared with Caucasians. Because UCP2 would link to insulin secretion and obesity, it might explain this ethnic difference. Here, we report that the UCP2 promoter with the A allele showed higher promoter activity in the INS-1 ␤-cell line. The frequency of the A allele is higher in our Japanese study than that in Caucasians. Type 2 diabetic patients with the A allele need insulin therapy earlier and showed higher frequency of insulin treatment. Moreover glucose-induced early insulin secretion is significantly lower in patients with the A allele. However, there was no difference in allele frequency between obese and lean type 2 diabetic patients. In conclusion, UCP2 promoter polymorphism ؊866G/A does not affect obesity in Japanese type 2 diabetic patients but affects its transcription in ␤-cells and modulates glucose-induced insulin secretion and eventually insulin requirement in Japanese type 2 diabetic patients. Higher A allele frequency in the Japanese population might partly explain the ethnic difference of insulin secretion capacity. Diabetes 53:482-485, 2004 T he major defects in type 2 diabetes are those in insulin secretion and insulin sensitivity (1). Obesity is obviously an important factor for insulin sensitivity or resistance. Morbidly obese subjects are very rare in the Japanese population, and mean BMI in Japanese type 2 diabetic patients is also smaller than that in Caucasians (2). On the other hand, insulin secretion capacity is reported to be lower in Japanese (3,4). These ethnic differences may be explained by differences in genetic background associated with both obesity and insulin secretion. Uncoupling protein 2 (UCP2) is a subtype of the UCP family that mediates mitochondrial proton leak (5). Thus, higher expression of UCP2 might lead to the consumption of excess energy and a lessening of obesity. However, higher expression of UCP2 in ␤-cells would lead to a decrease in ATP production and a defect in insulin secretion. Several lines of evidence, including knockout mice, have also indicated an important role of UCP2 in insulin secretion (6 -9). Because UCP2 is related to both obesity and insulin secretion, it will be a strong candidate gene for type 2 diabetes. UCP2 promoter polymorphism Ϫ866G/A has been reported to associate with its expression in adipose tissue and obesity in Caucasians (10). Therefore, we have investigated the promoter activity of each allele of UCP2 in an INS-1 ␤-cell line and the relationship between this polymorphism and clinical profiles of Japanese type 2 diabetic patients. RESEARCH DESIGN AND METHODSA total of 413 type 2 diabetic patients and 172 nondiabetic control s...

A small portion of GD patients harbored elevated serum IgG4 levels. They were older, had increased hypoechoic areas in the thyroid, and appeared to be responsive or prone to be hypothyroid after ATD treatment. Thus, the present study suggests the presence of a novel subtype of GD. Measuring serum IgG4 levels may help to distinguish this new entity and provide potential therapeutic options for GD.

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OBJECTIVE -To determine genetic predispositions for diabetic polyneuropathy, we investigated the relationship between the Ϫ866G/A polymorphism of uncoupling protein (UCP) 2 and neurological manifestations in 197 type 2 diabetic patients.RESEARCH DESIGN AND METHODS -We first examined whether UCP2 mRNA had been expressed in the dorsal root ganglion (DRG) in four Long-Evans Tokushima Otsuka rats using RT-PCR and electrophoresis. Genotyping of UCP2 promoter polymorphism Ϫ866G/A was then performed in 197 unrelated Japanese type 2 diabetic patients, who were subjected to nerve conduction, quantitative vibratory perception, head-up tilt, and heart rate variability tests, by PCR restriction fragment-length polymorphism. The relationships between UCP2 genotype and various nerve functions were analyzed by uni-and multivariable analysis.RESULTS -Expression of UCP2 mRNA was confirmed in rat DRG. Multiple regression analysis clarified the hypothesis that the G/A ϩ A/A genotype was significantly related to decreased motor nerve conduction velocity and impaired blood pressure maintenance on the head-up tilt test. Multiple logistic regression analysis revealed that the G/A ϩ A/A genotypes are a significant risk factor for sensory nerve conduction slowing and orthostatic hypotension.CONCLUSIONS -UCP2 promoter gene polymorphism Ϫ866 G/A was significantly associated with nerve conduction slowing and vasomotor sympathetic functions. These findings suggest that the higher UCP2 activity related to the A allele has an energy-depleting effect on peripheral nerve function in type 2 diabetic patients. Diabetes Care 29:888 -894, 2006D iabetic peripheral polyneuropathy (DPN) is a multifactorial disorder arising from hyperglycemia and/or insulin deficiency. Advanced DPN causes serious complications, such as diabetic foot ulcers, gangrene, and Charcot joint, all of which reduce the quality of life of diabetic patients with DPN (1). Severe cardiovascular autonomic neuropathy also increases the risk of mortality (2). Therefore, elucidation of genetic predispositions for DPN is important for preventing DPN and inhibiting its progression. There are, however, few reports on the genetic predispositions for DPN (3-5).Oxidative damage due to hyperglycemia is reported to be one of the major factors contributing to the development of DPN (6). The main source of reactive oxygen species (ROS) in diabetes is thought to be the mitochondria (7). Uncoupling proteins (UCPs) can provide a controlled leak of protons across the inner membrane of the mitochondria and thus uncouple oxidative phosphorylation from respiration, with a concomitant decrease in inner mitochondrial membrane potential (8) and free radical generation (9,10). The mitochondrial UCP families, particularly UCP2, which is expressed in various human tissues, are thought to contribute to control of body temperature and energy metabolism as well as to regulation of mitochondrial production of ROS. Therefore, the UCP2 gene is considered to be involved in DPN.In experimental studies, the protective...