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PHARMACOLOGICAL INHIBITION OF GLUCOSYLCERAMIDE SYNTHASE ENHANCES INSULIN SENSITIVITY

¹Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam
²Macrozyme, Amsterdam
³Department of Clinical Biochemistry, University of Cambridge. Cambridge UK
⁴Centre for Liver, Digestive and Metabolic Disease, Academic Hospital Groningen, University of Groningen
⁵Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam
⁶Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University

Correspondence: j.m.aerts{at}amc.uva.nl

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 which catalyses 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 TNFalpha 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 normalised their elevated tissue glucosylceramide levels, markedly lowered circulating glucose levels, improved oral glucose tolerance, reduced glycated haemoglobin 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.

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