The prevalent Gly1057Asp polymorphism in the insulin receptor substrate-2 gene is not associated with impaired insulin secretion

Disruption of the insulin receptor substrate-2 was shown to cause type 2 di abetes in mice. This could be largely attributed to abnormal beta -cell dev elopment. In humans, a prevalent polymorphism. in insulin receptor substrat e-2 (Gly1057Asp) was not found be associated with type 2 diabetes in linkag e and association studies. We tested the hypothesis that an extreme challen ge of the beta cell might reveal subtle abnormalities in carriers of this p olymorphism undetected by conventional insulin secretion tests. Therefore, in addition to assessing beta -cell function by oral glucose tolerance test ing (n = 318, normal glucose tolerance), we measured the secretory response to maximal stimulation by hyperglycemia (10 mm), glucagonlike peptide-1, a nd arginine administered in an additive fashion (n = 77, nondiabetic). The allelic frequency of the Asp allele was similar to 37%. Neither the beta -c ell function indices from the oral glucose tolerance test nor the secretory response during the hyperglycemic clamp differed measurably between carrie rs and controls. Moreover, maximal plasma C-peptide concentrations in respo nse to the combined glucose, glucagonlike peptide-1, and arginine stimulus was not different between Gly/Gly (10,745 +/- 1,186 pmol/liter) and X/Asp ( 10,800 +/- 490 pmol/liter, P = 0.99). In conclusion, our findings strongly suggest that the Gly1057Asp polymorphism in insulin receptor substrate-2 is not associated with beta -cell dysfunction. The normal maximal insulin sec retory response makes it unlikely that this common polymorphism results in abnormal beta -cell development.