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 (IRS)-1 was fo und in some studies to have a higher prevalence in type 2 diabetic subjects than in control subjects. Previously, transfection of IRS-1 with this poly morphism into insulin-secreting cells resulted in a marked reduction of glu cose-stimulated insulin secretion compared with the wild-type transfected c ells. In the present study, we compared insulin secretion in well-matched n ormal glucose-tolerant subjects with and without this polymorphism. Several validated indexes of beta -cell function from the oral glucose tolerance t est were significantly lower in X/Arg (n = 31) compared with Gly/Gly (n = 1 81) (P between 0.002 and 0.05), whereas insulin sensitivity (measured with a euglycemic clamp) was not different. During a modified hyperglycemic clam p, insulin secretion rates were significantly lower in Gly/Arg (n = 8) comp ared 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 decreas ed insulin secretion in response to glucose but not with insulin sensitivit y. It is possible that this polymorphism causes insulin resistance at the l evel of the beta -cell and contributes to the polygenic etiology of type 2 diabetes.