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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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References

  1. Bogardus, C. Metabolic abnormalities in the development of non-insulin-dependent diabetes mellitus. in Diabetes Mellitus: A Fundamental and Clinical Text (eds LeRoith, D., Taylor, S.I. & Olefsky, G.M.) 459– 467 (Lippincott-Raven, New York, 1996).

    Google Scholar 

  2. Polonsky, K.S., Sturis, J. & Bell, G.I. Non-insulin-dependent diabetes mellitus—a genetically programmed failure of the Β cell to compensate for insulin resistance. N. Engl. J. Med. 334, 777– 783 (1996).

    Article  CAS  Google Scholar 

  3. Kahn, C.R., Vicent, D. & Doria, A. Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu. Rev. Med. 47, 509– 531 (1996).

    Article  CAS  Google Scholar 

  4. DeFronzo, R.A. Lilly lecture 1987. The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37, 667– 687 (1988).

    Article  CAS  Google Scholar 

  5. Reaven, G.M. Pathophysiology of insulin resistance in human disease. Physiol. Rev. 75, 473–486 (1995).

    Article  CAS  Google Scholar 

  6. Accili, D. et al. Early neonatal death in mice homozygous for a null allele of the insulin receptor gene. Nature Genet. 12, 106–109 (1996).

    Article  CAS  Google Scholar 

  7. Bruning, J.C. et al. Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88, 561–572 (1997).

    Article  CAS  Google Scholar 

  8. Wang, L. et al. Hyperinsulinemia but no diabetes in transgenic mice homozygously expressing the tyrosine kinase-deficient human insulin receptor. Biochem. Biophys. Res. Commun. 240, 446– 451 (1997).

    Article  CAS  Google Scholar 

  9. Nishiyama, T. et al. Expression of the gene encoding the tyrosine kinase-deficient human insulin receptor in transgenic mice. Gene 141, 187–192 (1994).

    Article  CAS  Google Scholar 

  10. Ebina, Y. et al. Replacement of lysine residue 1030 in the putative ATP-binding region of the insulin receptor abolishes insulin- and antibody-stimulated glucose uptake and receptor kinase activity. Proc. Natl Acad. Sci. USA 84, 704–708 (1987).

    Article  CAS  Google Scholar 

  11. Di Cola, G., Cool, M.H. & Accili, D. Hypoglycemic effect of insulin-like growth factor-1 in mice lacking insulin receptors. J. Clin. Invest. 99, 2538–2544 (1997).

    Article  CAS  Google Scholar 

  12. Unger, R.H. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44, 863– 870 (1995).

    Article  CAS  Google Scholar 

  13. Zhou, Y.P. & Grill, V.E. Long-term exposure of rat pancreatic islets to fatty acids inhibits glucose-induced insulin secretion and biosynthesis through a glucose fatty acid cycle. J. Clin. Invest. 93, 870–876 (1994).

    Article  CAS  Google Scholar 

  14. Uysal, K.T., Wiesbrock, S.M., Marino, M.W. & Hotamisligil, G.S. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389, 610– 614 (1997).

    Article  CAS  Google Scholar 

  15. Leibiger, I.B., Leibiger, B., Moede, T. & Berggren, P.O. Exocytosis of insulin promotes insulin gene transcription via the insulin receptor/PI-3 kinase/p70 s6 kinase and CaM kinase pathways. Mol. Cell 1, 933–938 (1998).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Araki, E. et al. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186–190 (1994).

    Article  CAS  Google Scholar 

  18. Tamemoto, H. et al. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182–186 (1994).

    Article  CAS  Google Scholar 

  19. Chang, P.Y. et al. Expression of a dominant-negative mutant human insulin receptor in the muscle of transgenic mice. J. Biol. Chem. 269, 16034–16040 (1994).

    CAS  PubMed  Google Scholar 

  20. Weber, T.M., Joost, H.G., Simpson, I.A. & Cushman, S.W. in The Insulin Receptor (Alan R. Liss, New York, 1988).

    Google Scholar 

  21. Tolman, E.L., Schworer, C.M. & Jefferson, L.S. Effects of hypophysectomy on amino acid metabolism and gluconeogenesis in the perfused rat liver. J. Biol. Chem. 248, 4552–4560 (1973).

    CAS  PubMed  Google Scholar 

  22. Cinti, S., Eberbach, S., Castellucci, M. & Accili, D. Lack of insulin receptors affects the formation of white adipose tissue in mice. A morphological and ultrastructural analysis. Diabetologia 41, 171–177 (1998).

    Article  CAS  Google Scholar 

  23. Boschero, A.C. et al. Oxotremorine-m potentiation of glucose-induced insulin release from rat islets involves M3 muscarinic receptors. Am. J. Physiol. 268, E336–342 (1995).

    CAS  PubMed  Google Scholar 

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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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  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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