Disruption of irs-2 causes type 2 diabetes in mice

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 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

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support SIMILAR CONTENT BEING VIEWED BY OTHERS DELETION OF IRS-1 LEADS TO GROWTH FAILURE AND INSULIN RESISTANCE WITH DOWNREGULATION OF LIVER AND MUSCLE INSULIN SIGNALING IN RATS Article

Open access 08 January 2025 BETA-CELL SPECIFIC _INSR_ DELETION PROMOTES INSULIN HYPERSECRETION AND IMPROVES GLUCOSE TOLERANCE PRIOR TO GLOBAL INSULIN RESISTANCE Article Open access 08

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references ACKNOWLEDGEMENTS 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. AUTHOR

INFORMATION Author notes * Dominic J. Withers and Julio Sanchez Gutierrez: These authors contributed equally to this work. AUTHORS AND AFFILIATIONS * the Department of Medicine, Howard

Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, 02215, Massachusetts, USA Dominic J. Withers, Julio Sanchez Gutierrez, Heather Towery, Deborah J. Burks, 

Yitao Zhang, Dolores Bernal, Sebastian Pons, Susan Bonner-Weir & Morris F. White * the Department of Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New

Haven, 06520, Connecticut, USA Jian-Ming Ren, Stephen Previs & Gerald I. Shulman Authors * Dominic J. Withers View author publications You can also search for this author inPubMed Google

Scholar * Julio Sanchez Gutierrez View author publications You can also search for this author inPubMed Google Scholar * Heather Towery View author publications You can also search for this

author inPubMed Google Scholar * Deborah J. Burks View author publications You can also search for this author inPubMed Google Scholar * Jian-Ming Ren View author publications You can also

search for this author inPubMed Google Scholar * Stephen Previs View author publications You can also search for this author inPubMed Google Scholar * Yitao Zhang View author publications

You can also search for this author inPubMed Google Scholar * Dolores Bernal View author publications You can also search for this author inPubMed Google Scholar * Sebastian Pons View author

publications You can also search for this author inPubMed Google Scholar * Gerald I. Shulman View author publications You can also search for this author inPubMed Google Scholar * Susan

Bonner-Weir View author publications You can also search for this author inPubMed Google Scholar * Morris F. White View author publications You can also search for this author inPubMed 

Google Scholar CORRESPONDING AUTHOR Correspondence to Morris F. White. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Withers, D., Gutierrez, J.,

Towery, H. _et al._ Disruption of IRS-2 causes type 2 diabetes in mice. _Nature_ 391, 900–904 (1998). https://doi.org/10.1038/36116 Download citation * Received: 24 November 1997 * Accepted:

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