Abnormal islet sphingolipid metabolism in type 1 diabetes

Laurits J. Holm, Lars Krogvold, Jane P. Hasselby, Simranjeet Kaur, Laura A. Claessens, Mark A. Russell, Clayton E. Mathews, Kristian F. Hanssen, Noel G. Morgan, Bobby P.C. Koeleman, Bart O. Roep, Ivan Gerling, Flemming Pociot, Knut Dahl-Jørgensen, Karsten Buschard

Research output: Contribution to journalArticle

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Abstract

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.

LanguageEnglish (US)
Pages1650-1661
Number of pages12
JournalDiabetologia
Volume61
Issue number7
DOIs
StatePublished - Jul 1 2018

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Sphingolipids
Type 1 Diabetes Mellitus
Sulfoglycosphingolipids
Inbred NOD Mouse
Fenofibrate
Autoimmunity
Islets of Langerhans
Genes
Proinsulin
Cell Physiological Phenomena
Genome-Wide Association Study
Genetic Predisposition to Disease
Fluorescence Microscopy
Single Nucleotide Polymorphism
Electron Microscopy
Animal Models
Cell Culture Techniques
Immunohistochemistry
Cell Proliferation
RNA

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Holm, L. J., Krogvold, L., Hasselby, J. P., Kaur, S., Claessens, L. A., Russell, M. A., ... Buschard, K. (2018). Abnormal islet sphingolipid metabolism in type 1 diabetes. Diabetologia, 61(7), 1650-1661. https://doi.org/10.1007/s00125-018-4614-2

Abnormal islet sphingolipid metabolism in type 1 diabetes. / 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; Pociot, Flemming; Dahl-Jørgensen, Knut; Buschard, Karsten.

In: Diabetologia, Vol. 61, No. 7, 01.07.2018, p. 1650-1661.

Research output: Contribution to journalArticle

Holm, LJ, Krogvold, L, Hasselby, JP, Kaur, S, Claessens, LA, Russell, MA, Mathews, CE, Hanssen, KF, Morgan, NG, Koeleman, BPC, Roep, BO, Gerling, I, Pociot, F, Dahl-Jørgensen, K & Buschard, K 2018, 'Abnormal islet sphingolipid metabolism in type 1 diabetes' Diabetologia, vol. 61, no. 7, pp. 1650-1661. https://doi.org/10.1007/s00125-018-4614-2
Holm LJ, Krogvold L, Hasselby JP, Kaur S, Claessens LA, Russell MA et al. Abnormal islet sphingolipid metabolism in type 1 diabetes. Diabetologia. 2018 Jul 1;61(7):1650-1661. https://doi.org/10.1007/s00125-018-4614-2
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 ; Pociot, Flemming ; Dahl-Jørgensen, Knut ; Buschard, Karsten. / Abnormal islet sphingolipid metabolism in type 1 diabetes. In: Diabetologia. 2018 ; Vol. 61, No. 7. pp. 1650-1661.
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