Studies of sulfatide expression in relation to beta cell function

Abstract

Previous studies have shown that the glycosphingolipid sulfatide (3´-sulfogalactosyl-ceramide) is present and functionally involved in pancreatic beta cells. In these cells, sulfatide is synthesised as two major isoforms, C16:0 and C24:0 sulfatide, with different length of the fatty acid chain of the ceramide moiety. Sulfatide and insulin are located to the secretory granules and follow the same intracellular trafficking route, and sulfatide is able to preserve insulin crystals and mediate the conversion of insulin hexamers to monomers under relevant physiological conditions. Sulfatide also influences insulin secretion by interacting with both proximal and distal regulatory steps of the insulin secretion machinery in beta cells. Diabetes mellitus results from the inability of insulin to reduce blood glucose levels, leading to hyperglycaemia, and occurs in two major forms. Type I diabetes is an autoimmune disease, in which the beta cells are selectively destroyed, and patients show high titers of sulfatide antibodies. Type II diabetes is characterised by impaired insulin secretion in combination with insulin resistance of target cells. Thus, sulfatide might be a factor to be considered in the pathology of both type I and type II diabetes.Sulfatide expression, metabolism and subcellular location in the pancreas of human and rodent models of diabetes and in cultured beta cells were investigated to further elucidate the possible role of sulfatide in beta cell function and diabetes. Lipid analysis in combination with immunocytochemical, electron microscopy and subcellular isolation techniques were used. In vivo administration of sulfatide to a pre-type II diabetes rat model was also performed, whereafter the effect on insulin release and glycaemic control was evaluated.The presence of sulfatide in adult pancreas was consistent in all rodents studied, and in human pancreas. Sulfatide was also present in human fetal and rodent neonatal pancreas, i.e. during the critical period of self and non-self discrimination. In neonatal and fetal pancreas and in the immature cultured beta cells another sulfated glycosphingolipid, sulfated lactosylceramide, was expressed. This glycosphingolipid was also found in pancreas of the adult type I diabetes animal models, indicating an immature phenotype of remaining beta cells. In the type II diabetes animal models and their respective background strains, sulfatide had an altered expression compared with other mammalian pancreas examined, involving the selective lack of the insulin crystal preserving C16:0 sulfatide isoform. The C16:0 sulfatide isoform was also shown to facilitate glucose stimulated insulin secretion in prediabetic Zucker fatty (fa/fa) rats in vivo, but appeared to have no effect on insulin sensitivity. Thus the selection of sulfatide isoforms in pancreas might be a genetic factor contributing to beta cell dysfunction in the type II diabetes animal models. The sulfatide expression and metabolism in the beta cell line RIN-38 was found to be similar to freshly isolated islets. Using this cell line, sulfatide and the insulin receptor was shown to be co-located to isolated detergent-insoluble membrane domains. In conclusion, these findings give further support to the possibility that sulfatide is a relevant autoantigen in type I diabetes and that the remaining beta cells in the type I diabetes models decline to a fetal mode of action. The C16:0 sulfatide isoform is involved in insulin crystal preservation and insulin secretion of beta cells, and the selective expression of this isoform might contribute to the development of type II diabetes. This study also supports that the RIN-38 cell line is an excellent model for further exploration of the role of sulfatide in beta cell function.