Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling

Nat Genet. 1999 Sep;23(1):32-40. doi: 10.1038/12631.


Insulin receptor substrates (Irs proteins) mediate the pleiotropic effects of insulin and Igf-1 (insulin-like growth factor-1), including regulation of glucose homeostasis and cell growth and survival. We intercrossed mice heterozygous for two null alleles (Irs1+/- and Irs2+/-) and investigated growth and glucose metabolism in mice with viable genotypes. Our experiments revealed that Irs-1 and Irs-2 are critical for embryonic and post-natal growth, with Irs-1 having the predominant role. By contrast, both Irs-1 and Irs-2 function in peripheral carbohydrate metabolism, but Irs-2 has the major role in beta-cell development and compensation for peripheral insulin resistance. To establish a role for the Igf-1 receptor in beta-cells, we intercrossed mice heterozygous for null alleles of Igf1r and Irs2. Our results reveal that Igf-1 receptors promote beta-cell development and survival through the Irs-2 signalling pathway. Thus, Irs-2 integrates the effects of insulin in peripheral target tissues with Igf-1 in pancreatic beta-cells to maintain glucose homeostasis.

Publication types

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

MeSH terms

  • Age Factors
  • Animals
  • Apoptosis
  • Blood Glucose / analysis
  • Body Weight
  • Female
  • Gene Expression Regulation, Developmental
  • Glucose Tolerance Test
  • Insulin / blood
  • Insulin / metabolism*
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Pancreas / metabolism
  • Phosphoproteins / metabolism*
  • Phosphoproteins / physiology*
  • Receptor, IGF Type 1 / metabolism*
  • Signal Transduction*
  • Time Factors


  • Blood Glucose
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, mouse
  • Phosphoproteins
  • Receptor, IGF Type 1