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Disruption of IRS-2 causes type 2 diabetes in mice


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 cytokines1. Disruption of IRS-1 in mice retards growth, but diabetes does not develop because insulin secretion increases to compensate for the mild resistance to insulin2,3. 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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Figure 1: Gene targeting of the IRS-2 locus.
Figure 2: Fasting blood glucose and glucose-tolerance test, fasting insulin levels and insulin-tolerance test, and in vivo glucose disposal and hepatic glucose production.
Figure 3: Expression and insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR), insulin-stimulated activation of PI(3)K and IRS association with p85, and expression of PI(3)K adaptor subunits in the liver and muscle of wild-type (WT), IRS-1−/− and IRS-2−/− mice.
Figure 4: Islet morphology and analysis of β-cell mass in IRS-2−/−, IRS-1−/− and wild-type mice, and expression of IRS-2 in islets of wild-type and IRS-2−/− mice.


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We thank A. Nagy for R1 cells; M. Ginsberg, M. Petruzelli and M. Taneja for technical support; B. Cheatham for the anti-IRβ antibody. Blastocyst injections were performed in the Core Laboratory of the Diabetes and Endocrinology Research Center, Vanderbilt University. This work was supported by grants from the NIH to G.I.S., S.B.W. and M.F.W. D.J.W. is supported by an MRC (UK) Clinician Scientist Fellowship. D.J.B. was supported by a grant from the JDFI. J.S.G. and D.B. were supported by grants from the Spanish Government.

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Correspondence to Morris F. White.

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Withers, D., Gutierrez, J., Towery, H. et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904 (1998).

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