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Abnormal islet sphingolipid metabolism in type 1 diabetes

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  1. Circulating metabolites in progression to islet autoimmunity and type 1 diabetes

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  2. Fenofibrate increases very-long-chain sphingolipids and improves blood glucose homeostasis in NOD mice

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  3. White coat hypertension in early pregnancy in women with pre-existing diabetes: prevalence and pregnancy outcomes

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  1. Linking glycemic dysregulation in diabetes to symptoms, comorbidities, and genetics through EHR data mining

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Fenofibrate increases very-long-chain sphingolipids and improves blood glucose homeostasis in NOD mice

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Pitfalls of histopathological evaluation of EUS guided microbiopsies from pancreatic cystic neoplasms

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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 .

Original languageEnglish
JournalDiabetologia
Volume61
Issue number7
Pages (from-to)1650-1661
Number of pages11
ISSN0012-186X
DOIs
Publication statusPublished - Jul 2018

    Research areas

  • Journal Article

ID: 53670101