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The –866A/A Genotype in the Promoter of the Human Uncoupling Protein 2 Gene Is Associated With Insulin Resistance and Increased Risk of Type 2 Diabetes

¹ Laboratory of Molecular Medicine, University of Rome, Rome, Italy
² Department of Internal Medicine, University of Rome, Rome, Italy
³ Division of Internal Medicine, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy
⁴ Department of Experimental and Clinical Medicine, Università Magna Græcia di Catanzaro, Catanzaro, Italy
⁵ Divisione di Chirurgia Generale, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Milan, Italy
⁶ Cattedra di Medicina Interna and Seconda Divisione di Medicina Interna, Universita di Milano, Ospedale San Paolo, Milan, Italy

Uncoupling protein (UCP)-2 is a member of the mitochondrial inner membrane carriers that uncouple pro-ton entry in the mitochondrial matrix from ATP synthesis. The –866G/A polymorphism in the UCP2 gene, which enhances its transcriptional activity, was associated with enhanced risk for type 2 diabetes in obese subjects. We addressed the question of whether the –866G/A polymorphism contributes to variation in insulin sensitivity by genotyping 181 nondiabetic offspring of type 2 diabetic patients. Insulin sensitivity, assessed by the hyperinsulinemic-euglycemic clamp, was reduced in –866A/A carriers compared with –866A/G or –866G/G carriers (P = 0.01). To directly investigate the correlation between UCP2 expression and insulin resistance, UCP2 mRNA levels were measured by real-time RT-PCR in subcutaneous fat obtained from 100 obese subjects who underwent laparoscopic adjustable gastric banding. UCP2 mRNA expression was significantly correlated with insulin resistance as assessed by the homeostasis model assessment index (r = 0.27, P = 0.007). We examined the association of the –866A/A genotype in a case-control study including 483 type 2 diabetic subjects and 565 control subjects. The –866A/A genotype was associated with diabetes in women (odds ratio 1.84, 95% CI 1.03–3.28; P = 0.037), but not in men. These results indicate that the –866A/A genotype of the UCP2 gene may contribute to diabetes susceptibility by affecting insulin sensitivity.

Abbreviations: CT, computerized tomography; HOMA, homeostasis model assessment; OGTT, glucose tolerance test; UCP, uncoupling protein; UTR, untranslated region

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