Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus

J Clin Invest. 2004 Oct;114(7):917-27. doi: 10.1172/JCI21484.


We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arcuate Nucleus of Hypothalamus / cytology
  • Arcuate Nucleus of Hypothalamus / metabolism*
  • Blood Glucose / metabolism
  • Body Weight
  • Caloric Restriction
  • Cell Division / physiology
  • Diet
  • Female
  • Glucose Intolerance / metabolism
  • Hyperlipidemias / metabolism
  • Insulin / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / physiology
  • Intracellular Signaling Peptides and Proteins
  • Islets of Langerhans / cytology
  • Islets of Langerhans / metabolism*
  • Leptin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • RNA, Messenger / metabolism
  • Signal Transduction / physiology
  • Tissue Distribution
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Blood Glucose
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, mouse
  • Leptin
  • Phosphoproteins
  • RNA, Messenger
  • Transcription Factors