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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.
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Contributeur : Mélanie Karli <>
Soumis le : jeudi 18 avril 2019 - 09:32:57
Dernière modification le : mardi 28 mai 2019 - 10:38:04




Joana Moitinho Oliveira, Sandra A Rebuffat, Rosa Gasa, Ramon Gomis. Targeting type 2 diabetes: lessons from a knockout model of insulin receptor substrate 2. Canadian Journal of Physiology and Pharmacology, NRC Research Press, 2014, 92 (8), pp.613-620. ⟨10.1139/cjpp-2014-0114⟩. ⟨hal-02103070⟩



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