Abnormal islet sphingolipid metabolism in type 1 diabetes

• Published in: Diabetologia Vol. 61; no. 7; pp. 1650 - 1661
• Main Authors: Holm, Laurits J., Krogvold, Lars, Hasselby, Jane P., Kaur, Simranjeet, Claessens, Laura A., Russell, Mark A., Mathews, Clayton E., Hanssen, Kristian F., Morgan, Noel G., Koeleman, Bobby P. C., Roep, Bart O., Gerling, Ivan C., Pociot, Flemming, Dahl-Jørgensen, Knut, Buschard, Karsten
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.07.2018; Springer Nature B.V; Springer Verlag
• Subjects: Adult; Animal models; Animals; Apoptosis; Autoimmune diseases; Autoimmunity; Beta cells; Biosynthesis; Case-Control Studies; Cell culture; Cell Proliferation; Cells, Cultured; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - prevention & control; Disease Models, Animal; Electron microscopy; Female; Fenofibrate; Fenofibrate - pharmacology; Gene Expression Regulation, Enzymologic; Genomes; Human Physiology; Humans; Immunofluorescence; Immunohistochemistry; Insulin; Insulin secretion; Internal Medicine; Islets of Langerhans; Islets of Langerhans - drug effects; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Islets of Langerhans - ultrastructure; Lipid metabolism; Lipid Metabolism - genetics; Lymphocyte Activation; Lymphocytes T; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolism; Mice, Inbred NOD; Pancreas; Peroxisome proliferator-activated receptors; Polymorphism, Genetic; Ribonucleic acid; RNA; Rodents; Single-nucleotide polymorphism; Sphingolipids; Sulfatide; Sulfoglycosphingolipids - metabolism; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transcription; Fenofibrate; Prevention; Gene polymorphisms; GWAS; Type 1 diabetes; Islet autoimmunity; Sphingolipid; NOD mice; T cells; Sulfatide
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-018-4614-2

Aims/hypothesis Sphingolipids 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. Methods We 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. Results We 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/interpretation These results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach. Data availability The 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 .