Pharmacological Inhibition of Glucosylceramide Synthase Enhances Insulin Sensitivity

  1. Johannes M. Aerts1,
  2. Roelof Ottenhoff2,
  3. Andrew S. Powlson3,
  4. Aldo Grefhorst4,
  5. Marco van Eijk2,
  6. Peter F. Dubbelhuis2,
  7. Jan Aten4,
  8. Folkert Kuipers5,
  9. Mireille J. Serlie6,
  10. Tom Wennekes7,
  11. Jaswinder K. Sethi3,
  12. Stephen O'Rahilly3 and
  13. Hermen S. Overkleeft7
  1. 1Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  2. 2Macrozyme, Amsterdam, the Netherlands
  3. 3Department of Clinical Biochemistry, University of Cambridge, Cambridge, U.K
  4. 4Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  5. 5Centre for Liver, Digestive, and Metabolic Disease, Academic Hospital Groningen, University of Groningen, Groningen, the Netherlands
  6. 6Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  7. 7Gorlaeus Laboratories, Leiden Institute of Chemistry, Leiden University, Leiden, the Netherlands
  1. Address correspondence and reprint requests to J.M. Aerts, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ, Amsterdam, Netherlands. E-mail: j.m.aerts{at}amc.uva.nl

Abstract

A growing body of evidence implicates ceramide and/or its glycosphingolipid metabolites in the pathogenesis of insulin resistance. We have developed a highly specific small molecule inhibitor of glucosylceramide synthase, an enzyme that catalyzes a necessary step in the conversion of ceramide to glycosphingolipids. In cultured 3T3-L1 adipocytes, the iminosugar derivative N-(5′-adamantane-1′-yl-methoxy)-pentyl-1-deoxynojirimycin (AMP-DNM) counteracted tumor necrosis factor-α–induced abnormalities in glycosphingolipid concentrations and concomitantly reversed abnormalities in insulin signal transduction. When administered to mice and rats, AMP-DNM significantly reduced glycosphingolipid but not ceramide concentrations in various tissues. Treatment of ob/ob mice with AMP-DNM normalized their elevated tissue glucosylceramide levels, markedly lowered circulating glucose levels, improved oral glucose tolerance, reduced A1C, and improved insulin sensitivity in muscle and liver. Similarly beneficial metabolic effects were seen in high fat–fed mice and ZDF rats. These findings provide further evidence that glycosphingolipid metabolites of ceramide may be involved in mediating the link between obesity and insulin resistance and that interference with glycosphingolipid biosynthesis might present a novel approach to the therapy of states of impaired insulin action such as type 2 diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 7 February 2007. DOI: 10.2337/db06-1619.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db06-1619.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 1, 2007.
    • Received November 18, 2006.
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  1. Diabetes vol. 56 no. 5 1341-1349
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