The Gly972-->Arg Amino Acid Polymorphism in IRS-1 Impairs Insulin Secretion in Pancreatic Beta Cells

J Clin Invest. 1999 Aug;104(3):357-64. doi: 10.1172/JCI5870.

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 Arg(972) substitution are characterized by lower fasting insulin and C-peptide levels compared with non-carriers, suggesting that the Arg(972) IRS-1 variant may contribute to impairment of insulin secretion. In this study, we stably overexpressed both wild-type IRS-1 (RIN-WT) and Arg(972) IRS-1 variant (RIN-Arg(972)) in RIN beta cells to investigate directly whether the polymorphism in codon 972 of IRS-1 impairs insulin secretion. The Arg(972) 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 Arg(972) IRS-1 variant did not alter the extent of either glucose- or insulin-stimulated tyrosine phosphorylation of recombinant IRS-1. However, RIN-Arg(972) 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-Arg(972) 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 Arg(972) 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 beta cells. More importantly, the results suggest that the common Arg(972) IRS-1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics*
  • Animals
  • Arginine / genetics*
  • Glucose / pharmacology
  • Glycine / genetics*
  • Humans
  • Insulin / genetics
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Insulin Secretion
  • Insulinoma / enzymology
  • Insulinoma / genetics
  • Insulinoma / metabolism
  • Intracellular Fluid / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / genetics*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Polymorphism, Genetic*
  • RNA, Messenger / metabolism
  • Rats
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Recombinant Proteins / biosynthesis
  • Recombinant Proteins / genetics
  • Substrate Specificity / genetics
  • Sulfonylurea Compounds / pharmacology
  • Transfection
  • Tumor Cells, Cultured
  • Tyrosine / metabolism

Substances

  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, rat
  • Irs2 protein, rat
  • Phosphoproteins
  • RNA, Messenger
  • Recombinant Proteins
  • Sulfonylurea Compounds
  • Tyrosine
  • Arginine
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin
  • Glucose
  • Glycine