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Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue

Nature Genetics volume 20, pages 294–298 (1998)Cite this article

Abstract

Type 2 diabetes is a complex metabolic disorder characterized by peripheral insulin resistance and impaired Β cell function1,2. Insulin resistance is inherited as a non-mendelian trait3. In genetically predisposed individuals, resistance of skeletal muscle and adipose tissue to insulin action precedes the onset of clinical diabetes, and is thought to contribute to hyperglycaemia by leading to impaired Β cell function and increased hepatic glucose production4,5. It is not clear whether Β cell and liver defects are also genetically determined2. To test the hypothesis that insulin resistance in muscle and fat is sufficient to cause type 2 diabetes in the absence of intrinsic Β cell and liver abnormality, we generated transgenic mice that were insulin-resistant in skeletal muscle and adipose tissue. These mice developed all the prodromal features of type 2 diabetes but, despite the compounded effect of peripheral insulin resistance and a mild impairment of Β cell function, failed to become diabetic. These findings indicate the need for a critical re-examination of the primary site(s) of insulin resistance in diabetes.

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Figure 1: Insulin signalling in Insr+/–,K1030M transgenic mice.
Figure 2: In vitro analysis of insulin action in adipose cells, muscle and liver.
Figure 3: In vivo analysis of insulin sensitivity and glucose tolerance.
Figure 4: Islet size and morphology in WT and Insr+/–,K1030M mice.
Figure 5: Mean±s.e.m. of insulin and glucose levels in mice of different genotypes.

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Acknowledgements

We thank P. Rogliani for help with the Pck2 measurements, J. Nakae for the analysis of insulin receptor expression in islets, I. Atwater and A. Cotterell for performing islet microdissection and perfusion experiments. We also thank C.R. Kahn for helpful comments and sharing unpublished information, S. Cushman for support and advice and K. Rother for critical reading of the manuscript. The work was supported in part by a grant from the American Diabetes Association and by a generous gift of Sigma Tau Corp. to D.A. D.L. is supported by a fellowship grant from the University of Rome 'La Sapienza'.

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Authors and Affiliations

  1. Developmental Endocrinology Branch, National Institute of Child Health and Human Development,National Institutes of Health, Bethesda, 20892, Maryland, USA

    Davide Lauro, Yoshiaki Kido & Domenico Accili

  2. Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Arthur L. Castle & Mary-Jane Zarnowski

  3. Institute for Enzyme Research, University of Tokushima, Tokushima, 770, Japan

    Hideki Hayashi & Yousuke Ebina

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  1. Davide Lauro
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  2. Yoshiaki Kido
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  6. Yousuke Ebina
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  7. Domenico Accili
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Correspondence to Domenico Accili.

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Lauro, D., Kido, Y., Castle, A. et al. Impaired glucose tolerance in mice with a targeted impairment of insulin action in muscle and adipose tissue. Nat Genet 20, 294–298 (1998). https://doi.org/10.1038/3112

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