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.

  • Commentary
  • Published:

Diacylglycerol-mediated insulin resistance

Nature Medicine volume 16, pages 400–402 (2010)Cite this article

Subjects

Abstract

Understanding the molecular mechanisms of insulin resistance remains a major medical challenge of the twenty-first century. Over the last half-century, many hypotheses have been proposed to explain insulin resistance, and, most recently, inflammation associated with alterations in adipocytokines has become the prevailing hypothesis. Here we discuss diacylglycerol-mediated insulin resistance as an alternative and unifying hypothesis to explain the most common forms of insulin resistance associated with obesity and type 2 diabetes mellitus, as well as lipodystrophy and aging.

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

Relevant articles

Open Access articles citing this article.

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 mechanisms of cellular insulin resistance in muscle and liver.
Figure 2: Mechanisms for intracellular diacylglycerol (DAG) accumulation in muscle and liver.

References

  1. International Diabetes Federation. http://www.idf.org/latest-diabetes-figures-paint-grim-global-picture/ (2009).

  2. Shulman, G.I. et al. N. Engl. J. Med. 322, 223–228 (1990).

    Article  CAS  Google Scholar 

  3. Cline, G.W. et al. N. Engl. J. Med. 341, 240–246 (1999).

    Article  CAS  Google Scholar 

  4. Rothman, D.L., Shulman, R.G. & Shulman, G.I. J. Clin. Invest. 89, 1069–1075 (1992).

    Article  CAS  Google Scholar 

  5. Magnusson, I., Rothman, D.L., Katz, L.D., Shulman, R.G. & Shulman, G.I. J. Clin. Invest. 90, 1323–1327 (1992).

    Article  CAS  Google Scholar 

  6. Roden, M. et al. Diabetes 49, 701–707 (2000).

    Article  CAS  Google Scholar 

  7. Landau, B.R. et al. J. Clin. Invest. 98, 378–385 (1996).

    Article  CAS  Google Scholar 

  8. Yalow, R.S. & Berson, S.A. J. Clin. Invest. 39, 1157–1175 (1960).

    Article  CAS  Google Scholar 

  9. Schenk, S., Saberi, M. & Olefsky, J.M. J. Clin. Invest. 118, 2992–3002 (2008).

    Article  CAS  Google Scholar 

  10. Shoelson, S.E., Lee, J. & Goldfine, A.B. J. Clin. Invest. 116, 1793–1801 (2006).

    Article  CAS  Google Scholar 

  11. Hotamisligil, G.S. Nature 444, 860–867 (2006).

    Article  CAS  Google Scholar 

  12. Hotamisligil, G.S. Int. J. Obes. (Lond.) 32 Suppl 7, S52–S54 (2008).

    Article  CAS  Google Scholar 

  13. Evans, J.L., Goldfine, I.D., Maddux, B.A. & Grodsky, G.M. Endocr. Rev. 23, 599–622 (2002).

    Article  CAS  Google Scholar 

  14. Kulkarni, R.N. et al. Cell 96, 329–339 (1999).

    Article  CAS  Google Scholar 

  15. Brüning, J.C. et al. Cell 88, 561–572 (1997).

    Article  Google Scholar 

  16. Randle, P.J., Garland, P.B., Hales, C.N. & Newsholme, E.A. Lancet 1, 785–789 (1963).

    Article  CAS  Google Scholar 

  17. Randle, P.J., Newsholme, E.A. & Garland, P.B. Biochem. J. 93, 652–665 (1964).

    Article  CAS  Google Scholar 

  18. Randle, P.J., Garland, P.B., Newsholme, E.A. & Hales, C.N. Ann. NY Acad. Sci. 131, 324–333 (1965).

    Article  CAS  Google Scholar 

  19. Roden, M. et al. J. Clin. Invest. 97, 2859–2865 (1996).

    Article  CAS  Google Scholar 

  20. Dresner, A. et al. J. Clin. Invest. 103, 253–259 (1999).

    Article  CAS  Google Scholar 

  21. Yu, C. et al. J. Biol. Chem. 277, 50230–50236 (2002).

    Article  CAS  Google Scholar 

  22. Griffin, M.E. et al. Diabetes 48, 1270–1274 (1999).

    Article  CAS  Google Scholar 

  23. Itani, S.I., Ruderman, N.B., Schmieder, F. & Boden, G. Diabetes 51, 2005–2011 (2002).

    Article  CAS  Google Scholar 

  24. Kim, J.K. et al. Proc. Natl. Acad. Sci. USA 98, 7522–7527 (2001).

    Article  CAS  Google Scholar 

  25. Kim, J.K. et al. J. Clin. Invest. 113, 756–763 (2004).

    Article  CAS  Google Scholar 

  26. Liu, L. et al. J. Clin. Invest. 117, 1679–1689 (2007).

    Article  CAS  Google Scholar 

  27. Choi, C.S. et al. J. Clin. Invest. 117, 1995–2003 (2007).

    Article  CAS  Google Scholar 

  28. Choi, C.S. et al. Proc. Natl. Acad. Sci. USA 104, 16480–16485 (2007).

    Article  CAS  Google Scholar 

  29. Kim, J.K. et al. J. Clin. Invest. 114, 823–827 (2004).

    Article  CAS  Google Scholar 

  30. Hoehn, K.L. et al. Cell Metab. 11, 70–76 (2010).

    Article  CAS  Google Scholar 

  31. Samuel, V.T. et al. J. Biol. Chem. 279, 32345–32353 (2004).

    Article  CAS  Google Scholar 

  32. Samuel, V.T. et al. J. Clin. Invest. 117, 739–745 (2007).

    Article  CAS  Google Scholar 

  33. Nagai, Y. et al. Cell Metab. 9, 252–264 (2009).

    Article  CAS  Google Scholar 

  34. Neschen, S. et al. Cell Metab. 2, 55–65 (2005).

    Article  CAS  Google Scholar 

  35. Choi, C.S. et al. J. Biol. Chem. 282, 22678–22688 (2007).

    Article  CAS  Google Scholar 

  36. Savage, D.B. et al. J. Clin. Invest. 116, 817–824 (2006).

    Article  CAS  Google Scholar 

  37. Zhang, D. et al. Proc. Natl. Acad. Sci. USA 104, 17075–17080 (2007).

    Article  CAS  Google Scholar 

  38. Weiss, R. et al. Lancet 362, 951–957 (2003).

    Article  CAS  Google Scholar 

  39. Petersen, K.F. et al. J. Clin. Invest. 109, 1345–1350 (2002).

    Article  CAS  Google Scholar 

  40. Luzi, L. et al. Am. J. Physiol. Endocrinol. Metab. 284, E274–E280 (2003).

    Article  CAS  Google Scholar 

  41. Morino, K. et al. J. Clin. Invest. 115, 3587–3593 (2005).

    Article  CAS  Google Scholar 

  42. Befroy, D.E. et al. Diabetes 56, 1376–1381 (2007).

    Article  CAS  Google Scholar 

  43. Petersen, K.F. et al. Science 300, 1140–1142 (2003).

    Article  CAS  Google Scholar 

  44. Chibalin, A.V. et al. Cell 132, 375–386 (2008).

    Article  CAS  Google Scholar 

  45. Petersen, K.F. et al. N. Engl. J. Med. 362, 1082–1089 (2009).

    Article  Google Scholar 

  46. Weisberg, S.P. et al. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  Google Scholar 

  47. Xu, H. et al. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  Google Scholar 

  48. Taubes, G. Science 325, 256–260 (2009).

    Article  CAS  Google Scholar 

  49. Petersen, K.F., Dufour, S., Befroy, D., Garcia, R. & Shulman, G.I. N. Engl. J. Med. 350, 664–671 (2004).

    Article  CAS  Google Scholar 

  50. Kim, J.K., Gavrilova, O., Chen, Y., Reitman, M.L. & Shulman, G.I. J. Biol. Chem. 275, 8456–8460 (2000).

    Article  CAS  Google Scholar 

  51. Petersen, K.F. et al. Diabetes 54, 603–608 (2005).

    Article  CAS  Google Scholar 

  52. Pedersen, B.K. & Febbraio, M.A. J. Appl. Physiol. 102, 814–816 (2007).

    Article  CAS  Google Scholar 

  53. Shoelson, S.E. J. Appl. Physiol. 102, 820 (2007).

    Article  Google Scholar 

  54. Ofei, F., Hurel, S., Newkirk, J., Sopwith, M. & Taylor, R. Diabetes 45, 881–885 (1996).

    Article  Google Scholar 

  55. Mayerson, A.B. et al. Diabetes 51, 797–802 (2002).

    Article  CAS  Google Scholar 

  56. Belfort, R. et al. N. Engl. J. Med. 355, 2297–2307 (2006).

    Article  CAS  Google Scholar 

  57. Neschen, S. et al. Diabetes 56, 1034–1041 (2007).

    Article  CAS  Google Scholar 

  58. Kim, J.K. et al. Diabetes 52, 1311–1318 (2003).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Internal Medicine and Cellular & Molecular Physiology, Derek M. Erion and Gerald I. Shulman are at the Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, USA.,

    Derek M Erion & Gerald I Shulman

Authors
  1. Derek M Erion
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gerald I Shulman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gerald I Shulman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Erion, D., Shulman, G. Diacylglycerol-mediated insulin resistance. Nat Med 16, 400–402 (2010). https://doi.org/10.1038/nm0410-400

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0410-400

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research