Insulin Receptor Substrate-I Variants in Non-Insulin-dependent Diabetes

Insulin receptor substrate-i (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of vari-ants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening in-cluded a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitu-tions were found among the 40 NLDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 pa-tients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an im-pairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyper-glycemic clamp) or insulin action (estimated by the eugly-cemic clamp). Of the three amino acid substitutions ob-served Ser892Gly is the most interesting one since it abol-ishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound pro-tein (GRB2), and thus could potentially influence some as-pects of signal tranduction and metabolic response to insu-lin. (J. Clin. Invest. 1994.94:1141-1146.) Key words: insulin receptor substrate-i * non-insulin-dependent diabete