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dc.contributor.authorHolm, LJ
dc.contributor.authorKrogvold, L
dc.contributor.authorHasselby, JP
dc.contributor.authorKaur, S
dc.contributor.authorClaessens, LA
dc.contributor.authorRussell, MA
dc.contributor.authorMathews, CE
dc.contributor.authorHanssen, KF
dc.contributor.authorMorgan, NG
dc.contributor.authorKoeleman, BPC
dc.contributor.authorRoep, BO
dc.contributor.authorGerling, IC
dc.contributor.authorPociot, F
dc.contributor.authorDahl-Jørgensen, K
dc.contributor.authorBuschard, K
dc.date.accessioned2018-04-24T11:30:56Z
dc.date.issued2018-04-18
dc.description.abstractAIMS/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 .en_GB
dc.description.sponsorshipThe DiViD study was funded by the South-Eastern Norway Regional Health Authority (grant to KD-J), the Novo Nordisk Foundation (grant to KD-J), and through the PEVNET (Persistent Virus Infection in Diabetes Network) Study Group funded by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 261441 PEVNET. Additional grant support from National Institutes of Health, UC4 DK104155, the JDRF (47-2013- 520), Dutch Diabetes Research Foundation, and Stichtingen_GB
dc.identifier.citationFirst published online: 18th April 2018en_GB
dc.identifier.doi10.1007/s00125-018-4614-2
dc.identifier.urihttp://hdl.handle.net/10871/32591
dc.language.isoenen_GB
dc.publisherSpringer Verlag (Germany)en_GB
dc.relation.sourceThe 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=0en_GB
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pubmed/29671030en_GB
dc.rights© The Author(s) 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.en_GB
dc.subjectFenofibrateen_GB
dc.subjectGWASen_GB
dc.subjectGene polymorphismsen_GB
dc.subjectIslet autoimmunityen_GB
dc.subjectNOD miceen_GB
dc.subjectPreventionen_GB
dc.subjectSphingolipiden_GB
dc.subjectSulfatideen_GB
dc.subjectT cellsen_GB
dc.subjectType 1 diabetesen_GB
dc.titleAbnormal islet sphingolipid metabolism in type 1 diabetesen_GB
dc.typeArticleen_GB
dc.date.available2018-04-24T11:30:56Z
dc.identifier.issn0012-186X
exeter.place-of-publicationGermanyen_GB
dc.descriptionThis is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.en_GB
dc.identifier.journalDiabetologiaen_GB


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