October 21, 2008; doi:10.1152/ajpendo.90634.2008.-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 ␤-glucosylceramide, ␤-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 ␤-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. glycolipids; immune response; natural killer T cells; type 2 diabetes THE CHRONIC INCREASE in inflammatory mediators observed in type 2 diabetes (T2DM) has been shown to affect not only tissues and blood vessel walls but also pancreatic ␤-cells (11). The hyperglycemic Cohen diabetes-sensitive (CDS) rat is a model of mild cytokine-mediated diabetes (34) The CDS rat develops postprandial hyperglycemia when fed a diabetogenic high-sucrose, copper-poor diet (HSD), characterized by elevated blood glucose and blunted insulin secretion in response to glucose loading (8,35,36). Glucose intolerance in these rats is associated with exocrine lesions, lipid deposition, and IL-1␤-positive macrophage infiltration in the exocrine pancreas (34). However, the way in which the immune system is involved in the development of diabetes in this model has not yet been elucidated. Natural killer T (NKT) cells, innate regulatory lymphocytes that express a conserved T-cell receptor, play important parts in diverse neoplastic, autoimmune, and infectious processes (3,22). NKT cells usually express an invariant T-cell receptor that recognizes glycolipids in the context of the major histocompatibility complex (MHC) class I-like molecule CD1d (13, 15). ␤-Glucosylceramide (GC) and ␤-lactosylceramide (LC) are naturally occurring glycosphingolipids that exert immunomodula...

BackgroundIt has been shown that the proportion of natural killer T cells is markedly elevated during liver regeneration and their activation under different conditions can modulate this process. As natural killer T cells and liver injury are central in liver regeneration, elucidating their role is important.MethodsThe aim of the current study is to explore the role of natural killer T cells in impaired liver regeneration. Concanvalin A was injected 4 days before partial hepatectomy to natural killer T cells- deficient mice or to anti CD1d1-treated mice. Ki-67 and proliferating cell nuclear antigen were used to measure hepatocytes proliferation. Expression of hepatic cyclin B1 and proliferating cell nuclear antigen were evaluated by Western Blot and liver injury was assessed by ALT and histology.ResultsNatural killer T cells- deficient or mice injected with anti CD1d antibodies exhibited reduced liver regeneration. These mice were considerably resistant to ConA-induced liver injury. In the absence of NKT cells hepatic proliferating cell nuclear antigen and cyclin B1 decreased in mice injected with Concanvalin A before partial hepatectomy. This was accompanied with reduced serum interleukin-6 levels.ConclusionsNatural killer T cells play an important role in liver regeneration, which is associated with cyclin B1 and interleukin-6.

Administration of GC delayed hepatic triglyceride accumulation and suppressed early adipogenic gene expression during the hepatic regenerative response. These changes are closely associated with early inhibition of liver regeneration and temporal alteration of cytokine secretion.