Disruption of IRS-2 causes type 2 diabetes in mice

DJ Withers, JS Gutierrez, H Towery, DJ Burks, JM Ren… - Nature, 1998 - nature.com
DJ Withers, JS Gutierrez, H Towery, DJ Burks, JM Ren, S Previs, Y Zhang, D Bernal, S Pons
Nature, 1998nature.com
Human type 2 diabetes is characterized by defects in both insulin action and insulin
secretion. It has been difficult to identify a single molecular abnormality underlying these
features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they
mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption
of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion
increases to compensate for the mild resistance to insulin,. Here we show that disruption of …
Abstract
Human type 2 diabetes is characterized by defects in both insulin action and insulin secretion. It has been difficult to identify a single molecular abnormality underlying these features. Insulin-receptor substrates (IRS proteins) may be involved in type 2 diabetes: they mediate pleiotropic signals initiated by receptors for insulin and other cytokines. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin,. Here we show that disruption of IRS-2 impairs both peripheral insulin signalling and pancreatic β-cell function. IRS-2-deficient mice show progressive deterioration of glucose homeostasis because of insulin resistance in the liver and skeletal muscle and a lack of β-cell compensation for this insulin resistance. Our results indicate that dysfunction of IRS-2 may contribute to the pathophysiology of human type 2 diabetes.
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