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Endothelial Nitric Oxide Synthase Polymorphisms Are Associated With Type 2 Diabetes and the Insulin Resistance Syndrome

¹ Diabetology, Endocrinology and Metabolic Disease Unit, Medicine Division, San Raffaele Scientific Institute, Milan, Italy
² Department of Science and Biomedical Technology, University of Milan, Milan, Italy
³ Nephrology, Dialysis and Hypertension Division, Chair of "Clinica Medica Generale e Terapia Medica," San Raffaele Scientific Institute, Milan, Italy
⁴ Department of "Informatica e Sistemistica," University of Pavia, Pavia, Italy
⁵ Biostatistics Unit, Medical Research Council, Cambridge, U.K
⁶ Vita-Salute University, San Raffaele Scientific Institute, Milan, Italy
⁷ Department of "Scienze Sanitarie Applicate e Psicocomportamentali," University of Pavia, Pavia, Italy
⁸ DiBit, San Raffaele Scientific Institute, Milan, Italy

Endothelial nitric oxide synthase (eNOS) variants were previously demonstrated in cardiovascular disease. To evaluate whether eNOS gene variants are associated with insulin resistance and type 2 diabetes, we evaluated polymorphisms in Exon7 (E298D), intron 18 (IVS18 + 27AC), and intron 23 (IVS23 + 10GT) in 159 type 2 diabetic patients without macrovascular complications and in 207 healthy control subjects. Samples for all hormonal and metabolic variables were obtained after an overnight fast. The D298 and IVS18 + 27C alleles, but not the IVS23 + 10GT variant, were significantly more frequent in type 2 diabetic patients than in control subjects. The two- and three-loci haplotype analysis showed that there is a statistically significant association between the eNOS variants and type 2 diabetes. No significant differences were observed in the clinical characteristics of type 2 diabetic patients according to genotypes (except for visceral obesity [waist-to-hip ratio], which was significantly more present in D298 homozygotes). Healthy control subjects homozygous for both D298 and IVS18 + 27C presented higher insulin, C-peptide, and nitric oxide levels, as well as higher HOMA (homeostasis model assessment) values than the double wild-type homozygotes, with values superimposable on those found in type 2 diabetic patients. In conclusion, we described a significant association between eNOS gene polymorphisms and type 2 diabetes, suggesting a new genetic susceptibility factor for hyperinsulinemia, insulin resistance, and type 2 diabetes.

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