Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity: a novel therapeutic approach to insulin resistance Chapter 5

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 adipocytes the iminosugar derivative N-(5’-adamantane-1’-ylmethoxy)-pentyl-1-deoxynojirimycin (AMP-DNM), enhanced insulin-stimulated glucose uptake and reversed TNF-alpha induced abnormalities in insulin signal transduction. When administered to mice, AMP-DNM significantly reduced glycosphingolipid but not ceramide concentrations in various tissues. Treatment of ob/ob mice with AMP-DNM for 7 days normalised their elevated tissue glucosylceramide levels, markedly lowered circulating glucose levels, improved oral glucose tolerance, improved insulin sensitivity in muscle and liver, reduced hepatic fat deposition and increased cell surface expression of GLUT4 on adipocytes. These findings provide evidence that metabolites of ceramide, rather than ceramide itself, 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.