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Disruption of IRS-2 causes type 2 diabetes in mice.

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.

Pubmed ID: 9495343


  • Withers DJ
  • Gutierrez JS
  • Towery H
  • Burks DJ
  • Ren JM
  • Previs S
  • Zhang Y
  • Bernal D
  • Pons S
  • Shulman GI
  • Bonner-Weir S
  • White MF



Publication Data

February 26, 1998

Associated Grants

  • Agency: NIDDK NIH HHS, Id: R01 DK040936

Mesh Terms

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