PT - JOURNAL ARTICLE AU - Stumvoll, Michael AU - Fritsche, Andreas AU - Volk, Annette AU - Stefan, Norbert AU - Madaus, Alexander AU - Maerker, Elke AU - Teigeler, Anna AU - Koch, Matthias AU - Machicao, Fausto AU - Häring, Hans TI - The Gly972Arg Polymorphism in the Insulin Receptor Substrate-1 Gene Contributes to the Variation in insulin Secretion in Normal Glucose-Tolerant Humans AID - 10.2337/diabetes.50.4.882 DP - 2001 Apr 01 TA - Diabetes PG - 882--885 VI - 50 IP - 4 4099 - http://diabetes.diabetesjournals.org/content/50/4/882.short 4100 - http://diabetes.diabetesjournals.org/content/50/4/882.full SO - Diabetes2001 Apr 01; 50 AB - 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.