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Disruption of IRS-2 causes type 2 diabetes in mice

Author

Listed:
  • Dominic J. Withers

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

  • Julio Sanchez Gutierrez

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

  • Heather Towery

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

  • Deborah J. Burks

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

  • Jian-Ming Ren

    (Howard Hughes Medical Institute, Yale University School of Medicine)

  • Stephen Previs

    (Howard Hughes Medical Institute, Yale University School of Medicine)

  • Yitao Zhang

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

  • Dolores Bernal

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

  • Sebastian Pons

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

  • Gerald I. Shulman

    (Howard Hughes Medical Institute, Yale University School of Medicine)

  • Susan Bonner-Weir

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

  • Morris F. White

    (Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School)

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 diabetes.

Suggested Citation

  • Dominic J. Withers & Julio Sanchez Gutierrez & Heather Towery & Deborah J. Burks & Jian-Ming Ren & Stephen Previs & Yitao Zhang & Dolores Bernal & Sebastian Pons & Gerald I. Shulman & Susan Bonner-Wei, 1998. "Disruption of IRS-2 causes type 2 diabetes in mice," Nature, Nature, vol. 391(6670), pages 900-904, February.
    • Handle: RePEc:nat:nature:v:391:y:1998:i:6670:d:10.1038_36116
    DOI: 10.1038/36116
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    Cited by:

    1. Vinod Nikhra, 2019. "Exploring the Mechanism of Insulin Action, Differential Insulin Sensitivity and Insulin Resistance," Current Research in Diabetes & Obesity Journal, Juniper Publishers Inc., vol. 12(2), pages 23-31, October.
    2. Yue Hu & Min Zhou & Kai Zhang & Xiangquan Kong & Xiaoyan Hu & Kang Li & Li Liu, 2014. "Lack of Association between Insulin Receptor Substrate2 rs1805097 Polymorphism and the Risk of Colorectal and Breast Cancer: A Meta-Analysis," PLOS ONE, Public Library of Science, vol. 9(1), pages 1-7, January.
    3. Preetam Guha Ray & Debasis Maity & Jinbo Huang & Henryk Zulewski & Martin Fussenegger, 2023. "A versatile bioelectronic interface programmed for hormone sensing," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. Xiaoyun Lei & Shi Huang, 2017. "Enrichment of minor allele of SNPs and genetic prediction of type 2 diabetes risk in British population," PLOS ONE, Public Library of Science, vol. 12(11), pages 1-13, November.

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