title: Targeting type 2 diabetes: lessons from a knockout model of insulin receptor substrate 2.
abstract: Insulin receptor substrate 2 (IRS2) is a widely expressed protein that regulates crucial biological processes including glucose metabolism, protein synthesis, and cell survival. IRS2 is part of the insulin - insulin-like growth factor (IGF) signaling pathway and mediates the activation of the phosphotidylinositol 3-kinase (PI3K)-Akt and the Ras-mitogen-activated protein kinase (MAPK) cascades in insulin target tissues and in the pancreas. The best evidence of this is that systemic elimination of the Irs2 in mice (Irs2(-/-)) recapitulates the pathogenesis of type 2 diabetes (T2D), in that diabetes arises as a consequence of combined insulin resistance and beta-cell failure. Indeed, work using this knockout mouse has confirmed the importance of IRS2 in the control of glucose homeostasis and especially in the survival and function of pancreatic beta-cells. These studies have shown that IRS2 is critically required for beta-cell compensation in conditions of increased insulin demand. Importantly, islets isolated from T2D patients exhibit reduced IRS2 expression, which supports the likely contribution of altered IRS2-dependent signaling to beta-cell failure in human T2D. For all these reasons, the Irs2(-/-) mouse has been and will be essential for elucidating the inter-relationship between beta-cell function and insulin resistance, as well as to delineate therapeutic strategies to protect beta-cells during T2D progression.
authors: a Diabetes and Obesity Research Laboratory, Institut d'Investigations Biomediques August Pi i Sunyer, Centre Esther Koplowitz, C/Rosselló, 149-153 08036 Barcelona, Spain.
authors: Joana Moitinho
authors: JM
authors: Oliveira
authors: Sandra A
authors: SA
authors: Rebuffat
authors: Rosa
authors: R
authors: Gasa
authors: Ramon
authors: R
authors: Gomis
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism*; D007333:Insulin Resistance; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D010179:Pancreas / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse
keywords: apoptose; apoptosis; beta-cell; cellules bêta; diabète de type 2; insulin receptor substrate 2; substrat du récepteur de l’insuline 2; survie; survival; type 2 diabetes