Insulin receptor substrate proteins and neuroendocrine function

Biochem Soc Trans. 2001 Aug;29(Pt 4):525-9. doi: 10.1042/bst0290525.


A family of insulin receptor substrate (IRS) proteins mediates the pleiotropic effects of insulin and insulin-like growth factor 1 (IGF-1) on cellular function by recruiting several intracellular signalling networks. Conventional murine knockout strategies have started to reveal distinct physiological roles for the IRS proteins. Deletion of Irs1 produces a mild metabolic phenotype with compensated insulin resistance but also causes marked growth retardation. In contrast, mice lacking IRS-2 display nearly normal growth but develop diabetes owing to a combination of peripheral insulin resistance and beta-cell failure. As well as the classical metabolic events regulated by insulin signalling pathways, studies in lower organisms have implicated insulin/IGF-1 signalling pathways in the control of food intake and reproductive function. Our analysis of IRS-2 knock-out mice shows that female mice are infertile owing to defects in the hypothalamus, pituitary and gonad. IRS-2(-/-) mice have small, anovulatory ovaries with reduced numbers of follicles. Levels of the pituitary hormones luteinizing hormone and prolactin and gonadal steroids are low in these animals. Pituitaries of IRS-2(-/-) animals are decreased in size and contain reduced numbers of gonadotrophs. Additionally, IRS-2(-/-) females display increased food intake and develop obesity, despite elevated leptin levels, suggesting abnormalities in hypothalamic function. Coupled with recent observations that brain-specific deletion of the insulin receptor causes a similar phenotype, these findings implicate IRS signalling pathways in the neuroendocrine regulation of reproduction and energy homeostasis.

Publication types

  • Review

MeSH terms

  • Animals
  • Energy Metabolism
  • Homeostasis
  • Humans
  • Insulin / physiology*
  • Insulin Receptor Substrate Proteins
  • Insulin-Like Growth Factor I / physiology
  • Intracellular Signaling Peptides and Proteins
  • Islets of Langerhans / physiology
  • Mice
  • Mice, Knockout
  • Neurosecretory Systems / physiology*
  • Phosphoproteins / metabolism
  • Phosphoproteins / physiology*
  • Receptor, Insulin / physiology*


  • IRS2 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, mouse
  • Phosphoproteins
  • Insulin-Like Growth Factor I
  • Receptor, Insulin