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-alpha-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.
journal_name
Diabetesjournal_title
Diabetesauthors
Aerts JM,Ottenhoff R,Powlson AS,Grefhorst A,van Eijk M,Dubbelhuis PF,Aten J,Kuipers F,Serlie MJ,Wennekes T,Sethi JK,O'Rahilly S,Overkleeft HSdoi
10.2337/db06-1619subject
Has Abstractpub_date
2007-05-01 00:00:00pages
1341-9issue
5eissn
0012-1797issn
1939-327Xpii
db06-1619journal_volume
56pub_type
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