Abstract
Aims/hypothesisSphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice.MethodsWe examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development.ResultsWe found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals.Conclusions/interpretationThese results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach.Data availabilityThe RNA expression data is available online at https://www.dropbox.com/s/93mk5tzl5fdyo6b/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%2C%20RNA%20expression.xlsx?dl=0. A list of SNPs identified is available at https://www.dropbox.com/s/yfojma9xanpp2ju/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%20SNP.xlsx?dl=0.
Highlights
Type 1 diabetes is characterised as an autoimmune disease in which autoreactive T cells infiltrate the pancreatic islets and destroy the insulin producing beta cells [1]
Sulfatide is known to participate in the regulation of firstphase insulin secretion [13] and it is possible that the observed loss of pancreatic sulfatide may contribute to the loss of firstphase insulin secretion seen during the development of type 1 diabetes [39]
We notice a finer granulation in the islets of individuals with type 1 diabetes; whether this might, in part, influence the reduced sulfatide-staining that is seen in insulin
Summary
Type 1 diabetes is characterised as an autoimmune disease in which autoreactive T cells infiltrate the pancreatic islets and destroy the insulin producing beta cells [1]. The potential importance of beta cell dysfunction, rather than complete beta cell loss, in the pathogenesis of type 1 diabetes has recently been emphasised by the demonstration that a majority of individuals with diabetes retain a significant proportion of insulinpositive islets at disease onset [2,3,4]. Using blood and tissue samples from pancreas biopsies from newly diagnosed individuals with type 1 diabetes, we found evidence suggesting that sphingolipid metabolism plays a role in type 1 diabetes pathology. Based on this we tested whether increasing pancreatic sulfatide levels could prevent and reverse experimental autoimmune diabetes in NOD mice
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