Disruption of IRS-2 Causes Type 2 Diabetes in Mice

Nature. 1998 Feb 26;391(6670):900-4. doi: 10.1038/36116.

Abstract

Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic beta-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of beta-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Cloning, Molecular
  • Diabetes Mellitus, Type 2 / etiology*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Female
  • Gene Targeting
  • Humans
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance
  • Intracellular Signaling Peptides and Proteins
  • Islets of Langerhans / physiopathology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / deficiency
  • Phosphoproteins / genetics
  • Phosphoproteins / physiology*
  • Phosphorylation
  • Receptor, Insulin / metabolism
  • Recombination, Genetic
  • Signal Transduction

Substances

  • Blood Glucose
  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • Phosphoproteins
  • Phosphatidylinositol 3-Kinases
  • Receptor, Insulin