The Gly⁹⁷²→Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic β cells

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Abstract

Recent studies have identified several polymorphisms in the human insulin receptor substrate-1 (IRS-1) gene. The most prevalent IRS-1 variant, a Gly→Arg change at the codon 972, has been reported to be increased in prevalence among patients with type 2 diabetes. Carriers of the Arg972 substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg972 IRS-1 variant may contribute to impairment of insulin secretion. In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg972 IRS-1 variant (RIN-Arg972) in RIN β cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. The Arg972 IRS-1 variant did not affect expression or function of endogenous IRS-2. RIN-WT showed a marked increase in both glucose- and insulin-stimulated tyrosine phosphorylation of IRS-1 compared with control RIN cells. The Arg972 IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. However, RIN-Arg972 showed a significant decrease in binding of the p85 subunit of phosphatidylinositol-3-kinase (PI 3-kinase) with IRS-1, compared with RIN-WT. Compared with control RIN cells, insulin content was reduced to the same extent in RIN-WT or RIN-Arg972 at both the protein and mRNA levels. Both glucose- and sulfonylurea-induced insulin secretion was increased in RIN-WT compared with control RIN cells. By contrast, RIN cells expressing Arg972 IRS-1 exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with RIN-WT. These data suggest that the insulin signaling pathway involving the IRS-1/PI 3-kinase may play an important role in the insulin secretory process in pancreatic β cells. More importantly, the results suggest that the common Arg972 IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant.

Authors

Ottavia Porzio, Massimo Federici, Marta Letizia Hribal, Davide Lauro, Domenico Accili, Renato Lauro, Patrizia Borboni, Giorgio Sesti