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Inhibiting Glycosphingolipid Synthesis Improves Glycemic Control and Insulin Sensitivity in Animal Models of Type 2 Diabetes

From Genzyme, Framingham, Massachusetts

Address correspondence and reprint requests to Seng H. Cheng, PhD, or Nelson S. Yew, PhD, Genzyme Corporation, 31 New York Ave., Framingham, MA 01701-9322. E-mail: seng.cheng{at}genzyme.com or nelson.yew{at}genzyme.com

Abbreviations: D-PDMP, D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol; DRM, detergent-resistant microdomain; Genz-123346, (1R,2R)-nonanoic acid[2-(2',3'-dihydro-benzo [1,4]; dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]-amide-L-tartaric acid salt; IRS-1, insulin receptor substrate 1; NB-DNJ, N-butyldeoxynojirimycin; PI 3-kinase, phosphatidylinositol 3-kinase; TLC, thin-layer chromatography; TNF-, tumor necrosis factor-

Previous reports have shown that glycosphingolipids can modulate the activity of the insulin receptor, and studies in transgenic mice suggest a link between altered levels of various gangliosides and the development of insulin resistance. Here, we show that an inhibitor of glycosphingolipid synthesis can improve glucose control and increase insulin sensitivity in two different diabetic animal models. In the Zucker diabetic fatty rat, the glucosylceramide synthase inhibitor (1R,2R)-nonanoic acid[2-(2',3'-dihydro-benzo [1, 4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]- amide-L-tartaric acid salt (Genz-123346) lowered glucose and A1C levels and improved glucose tolerance. Drug treatment also prevented the loss of pancreatic ß-cell function normally observed in the Zucker diabetic fatty rat and preserved the ability of the animals to secrete insulin. In the diet-induced obese mouse, treatment with Genz-123346 normalized A1C levels and improved glucose tolerance. Analysis of the phosphorylation state of the insulin receptor and downstream effectors showed increased insulin signaling in the muscles of the treated Zucker diabetic fatty rats and diet-induced obese mice. These results suggest that inhibiting glycosphingolipid synthesis can significantly improve insulin sensitivity and glucose homeostasis and may therefore represent a novel therapeutic approach for the treatment of type 2 diabetes.

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