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Am J Physiol Endocrinol Metab 296: E72-E78, 2009. First published October 21, 2008; doi:10.1152/ajpendo.90634.2008
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β-Glycosphingolipids improve glucose intolerance and hepatic steatosis of the Cohen diabetic rat

Ehud Zigmond,1,* Sarah W. Zangen,2,* Orit Pappo,3 Miriam Sklair-Levy,4 Gadi Lalazar,1 Lydia Zolotaryova,1 Itamar Raz,2 and Yaron Ilan1

1Liver Unit and 2Diabetes Unit, Department of Internal Medicine, 3Department of Pathology, and 4Department of Radiology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel

Submitted 28 July 2008 ; accepted in final form 7 October 2008

A link between altered levels of various gangliosides and the development of insulin resistance was described in transgenic mice. Naturally occurring glycosphingolipids were shown to exert immunomodulatory effects in a natural killer T (NKT) cell-dependent manner. This study examined whether glycosphingolipid-induced modulation of the immune system may reduce pancreatic and liver steatosis and stimulate insulin secretion in the Cohen diabetes-sensitive (CDS) rat, a lean model of non-insulin-resistant, nutritionally induced diabetes. Four groups of CDS rats fed a diabetogenic diet were treated with daily intraperitoneal injections of glycosphingolipids β-glucosylceramide, β-lactosylceramide, a combination of both (IGL), or vehicle (PBS) for up to 45 days. Immune modulation was assessed by fluorescence-activated cell sorting analysis of intrahepatic and intrasplenic lymphocytes. Steatosis was assessed by MRI imaging and histological examination of liver and pancreas, Blood glucose and plasma insulin concentrations were assessed during an oral glucose tolerance test. Administration of glycosphingolipids, particularly IGL, increased intrahepatic trapping of CD8 T and NKT lymphocytes. Pancreatic and liver histology were markedly improved and steatosis was reduced in all treated groups compared with vehicle-treated rats. Insulin secretion was restored after glycosphingolipid treatment, resulting in improved glucose tolerance. The immunomodulatory effect of β-glycosphingolipids improved the β-cell function of the hyperglycemic CDS rat. Thus our results suggest a role for the immune system in the pathogenesis of diabetes in this model.

glycolipids; immune response; natural killer T cells; type 2 diabetes


Address for reprint requests and other correspondence: Y. Ilan, Liver Unit, Dept. of Medicine, Hebrew University-Hadassah Medical Center, PO Box 12000, Jerusalem, Israel IL-91120 (e-mail: ilan{at}hadassah.org.il)






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