Autonomic neuropathy in IDDM patients is associated with reduced nocturnal falls in BP and UAE and with a stronger relationship of UAE to systolic BP. We suggest a pathogenetic role of autonomic neuropathy in the development of diabetic nephropathy through changes in nocturnal glomerular function and by enhanced kidney vulnerability to hemodynamic effects of BP.

It was reported that the common ؊866G/A polymorphism in the promoter of the human uncoupling protein-2 (UCP2) gene, which enhances its trascriptional activity, is associated with increased mRNA levels in human adipocytes and reduced risk of obesity. Studies in knockout mice and ␤-cells indicate that UCP2 may play a role in ␤-cell function. In this study, we addressed the question of whether the common ؊866G/A polymorphism in UCP2 gene contributes to the variation of insulin secretion in humans by genotyping 301 nondiabetic subjects who underwent an oral glucose tolerance test. Glucose-stimulated insulin secretion estimated by several indexes of ␤-cell function was significantly lower in carriers of the ؊866A/A genotype compared with ؊866A/G or ؊866G/G according to the dosage of the A allele (P ‫؍‬ 0.002-0.05). To investigate directly whether the UCP2 ؊866G/A polymorphism affects human islet function, pancreatic islets isolated from two ؊866G/G homozygous, seven ؊866G/A heterozygous, and one ؊866A/A homozygous nondiabetic donors were studied. Islets from ؊866A/A homozygous had lower insulin secretion in response to glucose stimulation as compared with ؊866G/G and ؊866G/A carriers. These results indicate that the common ؊866G/A polymorphism in the UCP2 gene may contribute to the biological variation of insulin secretion in humans.

Some controversy still exists about factors involved in the abnormal circadian pattern of blood pressure (BP) in diabetes, while prognostic value of non-dipping condition is being increasingly recognised. This study was aimed at evaluating the relative influence of autonomic neuropathy (AN) and albumin excretion on 24-h BP profile in type 1 and type 2 diabetes. We measured AN cardiovascular tests, 24-h ambulatory BP, and urinary albumin excretion rate (UAE) in 47 type 1 and 34 type 2 normotensive non-proteinuric diabetic patients. In type 1 diabetic patients day-night differences (⌬) in systolic and diastolic BP were lower in those with AN than in those without (3 ؎ 9 vs 10 ؎ 6%, P Ͻ 0.01, and 8 ؎ 9 vs 16 ؎ 6%, P Ͻ 0.001), and in univariate regression analysis they were inversely related to both autonomic score, index of degree of AN (r ‫؍‬ ؊0.61, P Ͻ 0.001 and r ‫؍‬ ؊0.65, P Ͻ 0.001), and to 24-h UAE (r ‫؍‬ ؊0.39, P Ͻ 0.01 and r ‫؍‬ ؊0.46, P Ͻ 0.001). In type 1 diabetic patients AN was also associated with lower nocturnal decrease in UAE (patients with AN vs without AN: ؊37 ؎ 214 vs 49 ؎ 37%, P Ͻ 0.05), and with a stronger relationship between simultaneous 24-h UAE and 24-h

The insulin receptor substrate-1 (IRS-1) gene has been considered a candidate for insulin resistance, type 2 diabetes, and coronary artery disease. To investigate the relationship between the common Gly(972)Arg IRS-1 variant and the presence of cardiovascular risk factors, 153 glucose-tolerant, unrelated offspring of type 2 diabetic patients were studied. There were no differences between Arg(972) IRS-1 carriers and noncarriers in age, gender, body mass index, waist/hip ratio, body composition, fasting glucose and insulin levels, and glucose or insulin levels during the oral glucose tolerance test. Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of Arg(972) IRS-1 (P < 0.03). Carriers of Arg(972) IRS-1 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides (P < 0.01), total/high density lipoprotein cholesterol ratio (P < 0.01), free fatty acid levels (P < 0.04), systolic blood pressure (P < 0.04), microalbuminuria (P < 0.003), and intima-media thickness (P < 0.02). These results suggest that the Arg(972) IRS-1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type 2 diabetes by producing a cluster of insulin resistance-related metabolic abnormalities.

We investigated the significance of Gly1057Asp and Leu647Val insulin receptor substrate (IRS)-2 polymorphisms in two Italian cohorts comprising 186 glucose-tolerant subjects and 240 subjects with type 2 diabetes from the Lazio region (i.e. representative of central Italy), and 123 glucose-tolerant subjects from the Sicily region (i.e. representative of south Italy). The allelic frequency of Gly1057Asp variant did not differ between diabetics (32.9%) and nondiabetic subjects, whatever their ethnicity was (35.8% and 33.7% from Lazio and Sicily, respectively). As compared with Gly/Gly subjects within each group, Asp/Asp individuals showed no differences in quantitative traits, including fasting insulin and C-peptide, and several indices of insulin sensitivity and secretion. Only one of the diabetic patients was heterozygous for the Leu647Val variant, and none of the control subjects carried this variant. This patient had three children who were also heterozygous for this variant. They were glucose tolerant, and their insulin sensitivity and insulin secretion indices were within the range of age-matched controls. We also analyzed IRS-2 function in fibroblasts from carriers of Gly1057Asp or Leu647Val variant. No defects in IRS-2 expression, insulin-stimulated phosphorylation, or binding to the p85 subunit of phosphatidylinositol 3-kinase were observed. These results strongly argue against a major role of IRS-2 polymorphisms in the pathogenesis of type 2 diabetes.