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The Prevalent Gly1057Asp Polymorphism in the Insulin Receptor Substrate-2 Gene Is Not Associated with Impaired Insulin Secretion

Medizinische Klinik, Abteilung für Endokrinologie, Stoffwechsel und Pathobiochemie, Eberhard-Karls-Universität, Tübingen, Germany

Address all correspondence and requests for reprints to: Dr. Michael Stumvoll, Medizinische Universitätsklinik, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail: Michael.Stumvoll{at}med.uni-tuebingen.de

Abstract

Disruption of the insulin receptor substrate-2 was shown to cause type 2 diabetes in mice. This could be largely attributed to abnormal ß-cell development. In humans, a prevalent polymorphism in insulin receptor substrate-2 (Gly1057Asp) was not found be associated with type 2 diabetes in linkage and association studies. We tested the hypothesis that an extreme challenge of the ß cell might reveal subtle abnormalities in carriers of this polymorphism undetected by conventional insulin secretion tests. Therefore, in addition to assessing ß-cell function by oral glucose tolerance testing (n = 318, normal glucose tolerance), we measured the secretory response to maximal stimulation by hyperglycemia (10 mM), glucagon-like peptide-1, and arginine administered in an additive fashion (n = 77, nondiabetic). The allelic frequency of the Asp allele was 37%. Neither the ß-cell function indices from the oral glucose tolerance test nor the secretory response during the hyperglycemic clamp differed measurably between carriers and controls. Moreover, maximal plasma C-peptide concentrations in response to the combined glucose, glucagon-like 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 ß-cell dysfunction. The normal maximal insulin secretory response makes it unlikely that this common polymorphism results in abnormal ß-cell development.

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