Background: 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. Objective 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. Research Design and Methods: Four groups of CDs rats fed a diabetogenic diet were treated with daily intraperitoneal injections of glycosphingolipids; -glucosylceramide, -lactosylceramide, a combination of both (IGL), or vehicle (PBS) for up to 45 days. Immune modulation was assessed by FACS 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. Results: 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 to vehicle treated rats. Insulin secretion was restored, following glycosphingolipids treatment resulting in improved glucose tolerance. Conclusions: The immunomodulatory effect of -glycosphingolipids improved the -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.