Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance

Nature Medicine volume 6, pages 924–928 (2000)Cite this article

Abstract

The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted1. Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors2. The specific genes involved are not yet known, but impaired glucose uptake in skeletal muscle is an early, genetically determined defect that is present in non-diabetic relatives of diabetic subjects3. The rate-limiting step in muscle glucose use is the transmembrane transport of glucose mediated by glucose transporter (GLUT) 4 (ref. 4), which is expressed mainly in skeletal muscle, heart and adipose tissue5. GLUT4 mediates glucose transport stimulated by insulin and contraction/exercise. The importance of GLUT4 and glucose uptake in muscle, however, was challenged by two recent observations. Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance6, homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span7. Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerance8. To determine the importance of glucose uptake into muscle for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles. A profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction resulted. These mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal glucose homeostasis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Molecular characterization of the muscle-G4KO mice.
Figure 2: Glucose uptake is reduced in muscle but is increased in liver in muscle-G4KO mice in vivo.
Figure 3: Muscle-G4KO (MG4KO) mice show insulin resistance and glucose intolerance.

Similar content being viewed by others

References

  1. O'Rahilly, S. Diabetes in midlife: planting genetic time bombs. Nature Med. 3, 1080–1081 (1997).

    Article  CAS  Google Scholar 

  2. Warram, J.H., Rich, S.S. & Krolewski, A.S. in Joslin's Diabetes Mellitus (eds. Kahn, C.R. & Weir, G.C.) (Lea and Febinger, Philadelphia, 1995).

    Google Scholar 

  3. DeFronzo, R.A. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev. 5, 177–269 (1997).

    Google Scholar 

  4. Cline, G.W. et al. Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N. Engl. J. Med. 341, 240–246 (1999).

    Article  CAS  Google Scholar 

  5. Bell, G.I. et al. Molecular biology of mammalian glucose transporters. Diabetes Care 13, 198–208 (1990).

    Article  CAS  Google Scholar 

  6. Stenbit, A.E. et al. GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. Nature Med. 3, 1096–1101 (1997).

    Article  CAS  Google Scholar 

  7. Katz, E.B., Stenbit, A.E., Hatton, K., DePinho, R. & Charron, M.J. Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature 377, 151–155 (1995).

    Article  CAS  Google Scholar 

  8. Bruning, J.C. et al. A muscle-specific insulin receptor knockout exhibits features of the metabolic syndrome of NIDDM without altering glucose tolerance. Mol. Cell 2, 559–569 (1998).

    Article  CAS  Google Scholar 

  9. Abel, E.D. et al. Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. J. Clin. Invest. 104, 1703–1714 (1999).

    Article  CAS  Google Scholar 

  10. Carruthers, A. Facilitated diffusion of glucose. Physiol. Rev. 70, 1135–1176 (1990).

    Article  CAS  Google Scholar 

  11. Holman, G.D. et al. Cell surface labeling of glucose transporter isoform GLUT4 by bis- mannose photolabel. Correlation with stimulation of glucose transport in rat adipose cells by insulin and phorbol ester. J. Biol. Chem. 265, 18172–18179 (1990).

    CAS  PubMed  Google Scholar 

  12. Goodyear, L.J. & Kahn, B.B. Exercise, glucose transport, and insulin sensitivity. Annu. Rev. Med. 49, 235–261 (1998).

    Article  CAS  Google Scholar 

  13. Hom, F.G., Goodner, C.J. & Berrie, M.A. A [3H]2-deoxyglucose method for comparing rates of glucose metabolism and insulin responses among rat tissues in vivo. Validation of the model and the absence of an insulin effect on brain. Diabetes 33, 141–152 (1984).

    Article  CAS  Google Scholar 

  14. Virkamaki, A., Rissanen, E., Hamalainen, S., Utriainen, T. & Yki-Jarvinen, H. Incorporation of [3-3H]glucose and 2-[1-14C]deoxyglucose into glycogen in heart and skeletal muscle in vivo: implications for the quantitation of tissue glucose uptake. Diabetes 46, 1106–1110 (1997).

    Article  CAS  Google Scholar 

  15. Parniak, M. & Kalant, N. Incorporation of glucose into glycogen in primary cultures of rat hepatocytes. Can. J. Biochem. Cell Biol. 63, 333–340 (1985).

    Article  CAS  Google Scholar 

  16. Wojtaszewski, J.F. et al. Exercise modulates postreceptor insulin signaling and glucose transport in muscle-specific insulin receptor knockout mice. J. Clin. Invest. 104, 1257–1264 (1999).

    Article  CAS  Google Scholar 

  17. Trask, R.V. & Billadello, J.J. Tissue-specific distribution and developmental regulation of M and B creatine kinase mRNAs. Biochim. Biophys. Acta 1049, 182–188 (1990).

    Article  CAS  Google Scholar 

  18. Charron, M.J., Brosius, F.C.d., Alper, S.L. & Lodish, H.F. A glucose transport protein expressed predominately in insulin-responsive tissues. Proc. Natl. Acad. Sci. USA 86, 2535–2539 (1989).

    Article  CAS  Google Scholar 

  19. Brosius, F.C.d., Briggs, J.P., Marcus, R.G., Barac-Nieto, M. & Charron, M.J. Insulin-responsive glucose transporter expression in renal microvessels and glomeruli. Kidney Int. 42, 1086–1092 (1992).

    Article  CAS  Google Scholar 

  20. Leloup, C. et al. Discrete brain areas express the insulin-responsive glucose transporter GLUT4. Brain Res. Mol. Brain Res. 38, 45–53 (1996).

    Article  CAS  Google Scholar 

  21. Young, M.E., Radda, G.K. & Leighton, B. Nitric oxide stimulates glucose transport and metabolism in rat skeletal muscle in vitro. Biochem. J. 322, 223–228 (1997).

    Article  CAS  Google Scholar 

  22. Etgen, G.J. Jr., Fryburg, D.A. & Gibbs, E.M. Nitric oxide stimulates skeletal muscle glucose transport through a calcium/contraction- and phosphatidylinositol-3-kinase-independent pathway. Diabetes 46, 1915–1919 (1997).

    Article  CAS  Google Scholar 

  23. Kim, J.K. et al. Redistribution of substrates to adipose tissue in mice with selective insulin resistance in muscle promotes obesity. J. Clin. Invest. 105, 1791–1797 (2000).

    Article  CAS  Google Scholar 

  24. Frevert, E.U. & Kahn, B.B. Protein kinase C isoforms epsilon, eta, delta and zeta in murine adipocytes: expression, subcellular localization and tissue-specific regulation in insulin-resistant states. Biochem. J. 316, 865–871 (1996).

    Article  CAS  Google Scholar 

  25. Hayashi, T., Hirshman, M.F., Kurth, E.J., Winder, W.W. & Goodyear, L.J. Evidence for 5′ AMP-activated protein kinase mediation of the effect of muscle contraction on glucose transport. Diabetes 47, 1369–1373 (1998).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank J. Winnay, S. Curtis, K. Miller, O. Boss, J. Ilany, T. Minnemann and E. Hadro for assistance with experiments. This work was supported by grants from the National Institutes of Health: DK43051 to B.B.K. and DK46200 to B.B.K. and B.B.L.; DK33201 and DK36836 (Joslin's Diabetes Endocrinology Research Center) to C.R.K.; AR45670 to L.J.G.; a feasibility grant from P30 DK46200 to E.D.A. and DK09817 to M.D.M. Other support included the Robert Wood Johnson Foundation (E.D.A.), the Alfediam Society and the Nestle Foundation (O.D.P.), the Sigrid Juselius Foundation (A.V.) and the American Diabetes Association (B.B.K.).

Author information

Authors and Affiliations

  1. Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Ariel Zisman, M. Dodson Michael, Franck Mauvais-Jarvis, Jørgen F.P. Wojtaszewski, Michael F. Hirshman, Antti Virkamaki, Laurie J. Goodyear & C. Ronald Kahn

  2. Endocrine Division, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, 02215, Massachusetts, USA

    Odile D. Peroni, E. Dale Abel, Bradford B. Lowell & Barbara B. Kahn

Authors
  1. Ariel Zisman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Odile D. Peroni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Dale Abel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Dodson Michael
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Franck Mauvais-Jarvis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bradford B. Lowell
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jørgen F.P. Wojtaszewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael F. Hirshman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Antti Virkamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Laurie J. Goodyear
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. C. Ronald Kahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Barbara B. Kahn
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Barbara B. Kahn.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zisman, A., Peroni, O., Abel, E. et al. Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med 6, 924–928 (2000). https://doi.org/10.1038/78693

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/78693

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing