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OBJECTIVE -- To determine genetic predispositions for diabetic polyneuropathy, we investigated the relationship between the -866G/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 -- 866G/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 + 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 + A/A genotypes are a significant risk factor for sensory nerve conduction slowing and orthostatic hypotension. CONCLUSIONS -- UCP2 promoter gene polymorphism -- 866 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. [ABSTRACT FROM AUTHOR]

Betacellulin (BTC) plays an important role in differentiation, growth, and antiapoptosis of pancreatic beta-cells. We characterized about 2.3 kb of the 5'-flanking region of human BTC gene and identified six polymorphisms (-2159A>G, -1449G>A, -1388C>T, -279C>A, -233G>C, and -226A>G). The G allele in the -226A>G polymorphism was more frequent in type 2 diabetic patients (n = 250) than in nondiabetic subjects (n = 254) (35.6% vs. 27.8%, P = 0.007), and the -2159G, -1449A, and -1388T alleles were in complete linkage disequilibrium with the -226G allele. The frequencies of the -279A and -233C alleles were low (7.0 and 2.0% in diabetic patients), and no significant differences were observed. In the diabetic group, insulin secretion ability, assessed by the serum C-peptide response to intravenous glucagon stimulation, was lower in patients with the -226G allele (G/G, 2.96 +/- 0.16 ng/ml; G/A, 3.65 +/- 0.18 ng/ml; A/A, 3.99 +/- 0.16 ng/ml at 5 min after stimulation; P = 0.008). Furthermore, in vitro functional analyses indicated that both the -226G and the -233C alleles caused an approximately 50% decrease in the promoter activity, but no effects of the -2159A>G, -1449G>A, -1388C>T, and -279C>A polymorphisms were observed. These results suggest that the -226A/G polymorphism of the BTC gene may contribute to the development of diabetes. [ABSTRACT FROM AUTHOR]

We have previously reported that Pro 198Leu missense polymorphism of the glutathione peroxidase 1 (GPx-1) gene was associated with arteriosclerosis via decreased antioxidative defense in Japanese type 2 diabetic patients. In this study, we investigated the relationship between Pro198Leu polymorphism and neurological manifestations. We determined the GPx-1 genotype in 173 unrelated Japanese type 2 diabetic patients, who were interviewed neurological symptoms, received physical examination, nerve conduction, quantitative vibratory perception, head-up tilt and heart rate variability tests, by PCR-restriction fragment-length polymorphism. The patients with obstructive arteriosclerosis were excluded. The relationships between GPx-1 genotype and neurological symptoms, sign and various nerve functions were analyzed by uni- and multi-variable analysis. Frequencies of Pro/Pro, Pro/Leu and Leu/Leu genotype were 86.5%, 13.5% and 0%, respectively. Prevalence of the painful leg cramp and calf grasping pain in Pro/Leu patients was significantly higher than those in Pro/Pro patients. Vibratory perception thresholds in Pro/Leu patients were significantly higher than Pro/Pro patients. Multiple regression analysis clarified that Pro/Leu genotype was significantly related with elevated virbratory perception threshold. Multiple logistic regression analysis revealed that Pro/Leu genotype was a significant risk factor for impaired vibratory perception, calf grasping pain and weak pulsation of the dorsal pedal artery. In conclusion, GPx-1 polymorphism Pro 198Leu was significantly associated with impaired vibratory perception and painful leg cramp. The pathophysiological mechanism may be related to a functional perfusion impairment in the lower legs via increased oxidative stress resulting from GPx-1 Pro/Leu genotype. [ABSTRACT FROM AUTHOR]

Abstract: The Met55Val polymorphism in the small ubiquitin-like modifier 4 (SUMO4) gene has been associated with susceptibility not only to type 1 diabetes, but also to type 2 diabetes and diabetic nephropathy. We tried to confirm the association with susceptibility to type 2 diabetes and to investigate its role in diabetic vascular complications. The polymorphism was genotyped in two independent Japanese samples (Wakayama and Tokyo) by the TaqMan method. Susceptibility to type 2 diabetes and prevalence of diabetic vascular complications (coronary heart disease, cerebral infarction, retinopathy, and nephropathy) were evaluated by case-control study and multivariate logistic regression analysis, respectively. There were no significant differences in the frequency of alleles or genotypes between patients and controls. The Val allele, however, was associated with higher prevalence of coronary heart disease in patients in both groups (Wakayama, n =423, odds ratio, 1.64; 95% confidence interval, 1.02–2.64; P =0.041; Tokyo, n =451, odds ratio, 1.58; 95% CI, 1.07–2.34; P =0.021, in an additive model, respectively). No significant associations were observed with other diabetic vascular complications. Although association of the polymorphism with susceptibility to type 2 diabetes or nephropathy was not replicated, an association of the polymorphism with risk of coronary heart disease in type 2 diabetes is suggested. [Copyright &y& Elsevier]

Abstract: Oxidative stress has been implicated in pancreatic β-cell damage, insulin resistance and vascular function in diabetic patients and the dysfunction of antioxidant enzymes may be associated with the pathogenesis of diabetes. Extracellular superoxide dismutase (EC-SOD) is found in the extracellular matrix of tissues and the major scavenger of superoxide radical. To investigate the role of genetic variability for the pathogenesis of type 2 diabetes, we scanned the protein coding exon and flanking introns of EC-SOD gene for mutation in Japanese type 2 diabetic patients. We identified two missense mutations, Ala40Thr (GCG→ACG) and Arg213Gly (CGG→GGG), and a silent mutation, Leu53Leu (CTG→TTG). For one of these variants, the Ala40Thr polymorphism, the frequency of Thr allele and the number of subjects with Thr allele (Ala/Thr+Thr/Thr) were higher in type 2 diabetic patients (n =205) than those in non-diabetic subjects (n =220) (33.2% versus 24.1%, p =0.003 and 55.6% versus 42.7%, p =0.008, respectively). The patients with Thr allele also showed earlier age at diagnosis of diabetes (42.2±7.8 years versus 44.4±6.9 years, p =0.037) and higher prevalence of hypertension (53.5% versus 38.5%, p =0.032) than those without the allele. Insulin sensitivity, furthermore, was evaluated in 71 type 2 diabetic patients with short insulin tolerance test (SITT). The patients with Thr allele showed lower insulin sensitivity (Kitt value of SITT) than those without the allele (1.78±0.78%/min versus 2.33±1.02%/min, p =0.012), although no significant differences in other clinical and biochemical characteristics were observed between two groups. These results suggest that the genetic variant of EC-SOD gene is associated with insulin resistance and the susceptibility to type 2 diabetes. [Copyright &y& Elsevier]