The Gly972Arg Polymorphism in the Insulin Receptor Substrate-1 Gene Contributes to the Variation in insulin Secretion in Normal Glucose-Tolerant Humans

The Gly972Arg Polymorphism in the Insulin Receptor Substrate-1 Gene Contributes to the Variation in insulin Secretion in Normal Glucose-Tolerant Humans Michael Stumvoll , Andreas Fritsche , Annette Volk , Norbert Stefan , Alexander Madaus , Elke Maerker , Anna Teigeler , Matthias Koch , Fausto Machicao and Hans Häring Medical Clinic, Department of Endocrinology, Metabolism, and Pathobiochemistry, University of Tübingen, Germany Abstract The Gly972Arg polymorphism in the insulin receptor substrate (IRS)-1 was found in some studies to have a higher prevalence in type 2 diabetic subjects than in control subjects. Previously, transfection of IRS-1 with this polymorphism into insulin-secreting cells resulted in a marked reduction of glucose-stimulated insulin secretion compared with the wild-type transfected cells. In the present study, we compared insulin secretion in well-matched normal glucose-tolerant subjects with and without this polymorphism. Several validated indexes of β-cell function from the oral glucose tolerance test were significantly lower in X/Arg ( n = 31) compared with Gly/Gly ( n = 181) ( P between 0.002 and 0.05), whereas insulin sensitivity (measured with a euglycemic clamp) was not different. During a modified hyperglycemic clamp, insulin secretion rates were significantly lower in Gly/Arg ( n = 8) compared with Gly/Gly ( n = 36) during the first phase (1,711 ± 142 vs. 3,014 ± 328 pmol/min, P = 0.05) and after maximal stimulation with arginine (5,340 ± 639 vs. 9,075 ± 722 pmol/min, P = 0.03). In summary, our results suggest that the Gly972Arg polymorphism in IRS-1 is associated with decreased insulin secretion in response to glucose but not with insulin sensitivity. It is possible that this polymorphism causes insulin resistance at the level of the β-cell and contributes to the polygenic etiology of type 2 diabetes. CIR30, corrected insulin response after 30 min CPAUC, C-peptide area under the curve GAUC, glucose area under the curve GLP-1, glucagon-like peptide 1 IAUC, insulin area under the curve, IRS, insulin receptor substrate ISI, insulin sensitivity index IVGTT, intravenous glucose tolerance test MCR, metabolic clearance rate of glucose OGTT, oral glucose tolerance tests PI3-K, phosphatidylinositol 3-kinase Footnotes Address correspondence and reprint requests to Dr. Michael Stumvoll, Medizinische Universitätsklinik, Otfried-Mühller-Str. 10, D-72076 Tübingen, Germany. Email: Michael.Stumvoll{at}med.uni-tuebingen.de . Received for pub