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 C. Gerling; Flemming Pociot; Knut Dahl-Jørgensen; Karsten Buschard

doi:10.1007/s00125-018-4614-2

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 C. Gerling, Flemming Pociot, Knut Dahl-Jørgensen, Karsten Buschard^*

^*Corresponding author af dette arbejde

21 Citationer (Scopus)

49 Downloads (Pure)

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.

Originalsprog	Engelsk
Tidsskrift	Diabetologia
Vol/bind	61
Udgave nummer	7
Sider (fra-til)	1650-1661
Antal sider	12
ISSN	0012-186X
DOI	https://doi.org/10.1007/s00125-018-4614-2
Status	Udgivet - 2018

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10.1007/s00125-018-4614-2Licens: CC BY

Abnormal islet sphingolipid metabolism in type 1 diabetesForlagets udgivne version, 1,57 MBLicens: CC BY

Citationsformater

Holm, L. J., Krogvold, L., Hasselby, J. P., Kaur, S., Claessens, L. A., Russell, M. A., Mathews, C. E., Hanssen, K. F., Morgan, N. G., Koeleman, B. P. C., Roep, B. O., Gerling, I. C., Pociot, F., Dahl-Jørgensen, K., & 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

@article{e88428f872144d71937f0b620b720680,

title = "Abnormal islet sphingolipid metabolism in type 1 diabetes",

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.",

keywords = "Fenofibrate, Gene polymorphisms, GWAS, Islet autoimmunity, NOD mice, Prevention, Sphingolipid, Sulfatide, T cells, Type 1 diabetes",

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

year = "2018",

doi = "10.1007/s00125-018-4614-2",

language = "English",

volume = "61",

pages = "1650--1661",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer",

number = "7",

}

TY - JOUR

T1 - Abnormal islet sphingolipid metabolism in type 1 diabetes

AU - Holm, Laurits J.

AU - Krogvold, Lars

AU - Hasselby, Jane P.

AU - Kaur, Simranjeet

AU - Claessens, Laura A.

AU - Russell, Mark A.

AU - Mathews, Clayton E.

AU - Hanssen, Kristian F.

AU - Morgan, Noel G.

AU - Koeleman, Bobby P.C.

AU - Roep, Bart O.

AU - Gerling, Ivan C.

AU - Pociot, Flemming

AU - Dahl-Jørgensen, Knut

AU - Buschard, Karsten

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

KW - Fenofibrate

KW - Gene polymorphisms

KW - GWAS

KW - Islet autoimmunity

KW - NOD mice

KW - Prevention

KW - Sphingolipid

KW - Sulfatide

KW - T cells

KW - Type 1 diabetes

U2 - 10.1007/s00125-018-4614-2

DO - 10.1007/s00125-018-4614-2

M3 - Journal article

C2 - 29671030

AN - SCOPUS:85045652863

SN - 0012-186X

VL - 61

SP - 1650

EP - 1661

JO - Diabetologia

JF - Diabetologia

IS - 7

ER -

Abnormal islet sphingolipid metabolism in type 1 diabetes

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