Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 7/2018

Open Access 01-07-2018 | Article

Abnormal islet sphingolipid metabolism in type 1 diabetes

Authors: 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

Published in: Diabetologia | Issue 7/2018

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
van Belle TL, Coppieters KT, von Herrath MG (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev 91:79–118CrossRefPubMed
2.
Leete P, Willcox A, Krogvold L et al (2016) Differential insulitic profiles determine the extent of beta-cell destruction and the age at onset of type 1 diabetes. Diabetes 65:1362–1369CrossRefPubMed
3.
Krogvold L, Wiberg A, Edwin B et al (2016) Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia 59:492–501CrossRefPubMed
4.
Coppieters KT, Dotta F, Amirian N et al (2012) Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 209:51–60CrossRefPubMedPubMedCentral
5.
Krogvold L, Skog O, Sundstrom G et al (2015) Function of isolated pancreatic islets from patients at onset of type 1 diabetes: insulin secretion can be restored after some days in a nondiabetogenic environment in vitro: results from the DiViD study. Diabetes 64:2506–2512CrossRefPubMed
6.
Malmegrim KC, de Azevedo JT, Arruda LC et al (2017) Immunological balance is associated with clinical outcome after autologous hematopoietic stem cell transplantation in type 1 diabetes. Front Immunol 8:167CrossRefPubMedPubMedCentral
7.
8.
Chen Y, Liu Y, Sullards MC, Merrill AH Jr (2010) An introduction to sphingolipid metabolism and analysis by new technologies. NeuroMolecular Med 12:306–319CrossRefPubMedPubMedCentral
9.
Yamaji T, Hanada K (2015) Sphingolipid metabolism and interorganellar transport: localization of sphingolipid enzymes and lipid transfer proteins. Traffic 16:101–122CrossRefPubMed
10.
11.
Veret J, Bellini L, Giussani P, Ng C, Magnan C, Le Stunff H (2014) Roles of sphingolipid metabolism in pancreatic beta cell dysfunction induced by lipotoxicity. J Clin Med 3:646–662CrossRefPubMedPubMedCentral
12.
13.
Buschard K, Blomqvist M, Mansson JE, Fredman P, Juhl K, Gromada J (2006) C16:0 sulfatide inhibits insulin secretion in rat beta-cells by reducing the sensitivity of KATP channels to ATP inhibition. Diabetes 55:2826–2834CrossRefPubMed
14.
Buschard K, Bracey AW, McElroy DL et al (2016) Sulfatide preserves insulin crystals not by being integrated in the lattice but by stabilizing their surface. J Diabetes Res 2016:6179635CrossRefPubMedPubMedCentral
15.
Krogvold L, Edwin B, Buanes T et al (2014) Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study. Diabetologia 57:841–843CrossRefPubMed
16.
Osterbye T, Funda DP, Fundova P, Mansson JE, Tlaskalova-Hogenova H, Buschard K (2010) A subset of human pancreatic beta cells express functional CD14 receptors: a signaling pathway for beta cell-related glycolipids, sulfatide and beta-galactosylceramide. Diabetes Metab Res Rev 26:656–667CrossRefPubMed
17.
18.
Campbell-Thompson M, Wasserfall C, Kaddis J et al (2012) Network for Pancreatic Organ Donors with Diabetes (nPOD): developing a tissue biobank for type 1 diabetes. Diabetes Metab Res Rev 28:608–617CrossRefPubMedPubMedCentral
19.
Richardson SJ, Rodriguez-Calvo T, Gerling IC et al (2016) Islet cell hyperexpression of HLA class I antigens: a defining feature in type 1 diabetes. Diabetologia 59:2448–2458CrossRefPubMedPubMedCentral
20.
Wu J, Kakoola DN, Lenchik NI, Desiderio DM, Marshall DR, Gerling IC (2012) Molecular phenotyping of immune cells from young NOD mice reveals abnormal metabolic pathways in the early induction phase of autoimmune diabetes. PLoS One 7:e46941CrossRefPubMedPubMedCentral
21.
Onengut-Gumuscu S, Chen WM, Burren O et al (2015) Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat Genet 47:381–386CrossRefPubMedPubMedCentral
22.
Rosenbloom KR, Sloan CA, Malladi VS et al (2013) ENCODE data in the UCSC Genome Browser: year 5 update. Nucleic Acids Res 41:D56–D63CrossRefPubMed
23.
24.
Consortium G (2015) Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348:648–660CrossRef
25.
26.
Westra HJ, Peters MJ, Esko T et al (2013) Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45:1238–1243CrossRefPubMedPubMedCentral
27.
Franken KL, Hiemstra HS, van Meijgaarden KE et al (2000) Purification of his-tagged proteins by immobilized chelate affinity chromatography: the benefits from the use of organic solvent. Protein Expr Purif 18:95–99CrossRefPubMed
28.
Kracht MJ, van Lummel M, Nikolic T et al (2017) Autoimmunity against a defective ribosomal insulin gene product in type 1 diabetes. Nat Med 23:501–507CrossRefPubMed
29.
Hanada K (2003) Serine palmitoyltransferase, a key enzyme of sphingolipid metabolism. Biochim Biophys Acta 1632:16–30CrossRefPubMed
30.
Siow D, Sunkara M, Dunn TM, Morris AJ, Wattenberg B (2015) ORMDL/serine palmitoyltransferase stoichiometry determines effects of ORMDL3 expression on sphingolipid biosynthesis. J Lipid Res 56:898–908CrossRefPubMedPubMedCentral
31.
Han G, Gupta SD, Gable K et al (2009) Identification of small subunits of mammalian serine palmitoyltransferase that confer distinct acyl-CoA substrate specificities. Proc Natl Acad Sci U S A 106:8186–8191CrossRefPubMedPubMedCentral
32.
33.
Floyel T, Kaur S, Pociot F (2015) Genes affecting beta-cell function in type 1 diabetes. Curr Diab Rep 15:97CrossRefPubMed
34.
Mirza AH, Kaur S, Brorsson CA, Pociot F (2014) Effects of GWAS-associated genetic variants on lncRNAs within IBD and T1D candidate loci. PLoS One 9:e105723CrossRefPubMedPubMedCentral
35.
Baranowski M, Gorski J (2011) Heart sphingolipids in health and disease. Adv Exp Med Biol 721:41–56CrossRefPubMed
36.
Barrett JC, Clayton DG, Concannon P et al (2009) Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41:703–707CrossRefPubMedPubMedCentral
37.
Nakajima T, Kamijo Y, Yuzhe H et al (2013) Peroxisome proliferator-activated receptor alpha mediates enhancement of gene expression of cerebroside sulfotransferase in several murine organs. Glycoconj J 30:553–560CrossRefPubMed
38.
Crevecoeur I, Gudmundsdottir V, Vig S et al (2017) Early differences in islets from prediabetic NOD mice: combined microarray and proteomic analysis. Diabetologia 60:475–489CrossRefPubMed
39.
Sosenko JM, Skyler JS, Beam CA et al (2013) Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants. Diabetes 62:4179–4183CrossRefPubMedPubMedCentral
40.
Laviad EL, Albee L, Pankova-Kholmyansky I et al (2008) Characterization of ceramide synthase 2: tissue distribution, substrate specificity, and inhibition by sphingosine 1-phosphate. J Biol Chem 283:5677–5684CrossRefPubMed
41.
Subramanian L, Blumenfeld H, Tohn R et al (2012) NKT cells stimulated by long fatty acyl chain sulfatides significantly reduce the incidence of type 1 diabetes in nonobese diabetic mice [corrected]. PLoS One 7:e37771CrossRefPubMedPubMedCentral
42.
Exley MA, Bigley NJ, Cheng O et al (2001) CD1d-reactive T cell activation leads to amelioration of disease caused by diabetogenic encephalomyocarditis virus. J Leukoc Biol 69:713–718PubMed
43.
Doerr J, Bockenhoff A, Ewald B et al (2015) Arylsulfatase A overexpressing human iPSC-derived neural cells reduce CNS sulfatide storage in a mouse model of metachromatic leukodystrophy. Mol Ther 23:1519–1531CrossRefPubMedPubMedCentral
44.
Dotta F, Falorni A, Tiberti C et al (1997) Autoantibodies to the GM2-1 islet ganglioside and to GAD-65 at type 1 diabetes onset. J Autoimmun 10:585–588CrossRefPubMed
45.
Jessup CF, Bonder CS, Pitson SM, Coates PT (2011) The sphingolipid rheostat: a potential target for improving pancreatic islet survival and function. Endocr Metab Immune Disord Drug Targets 11:262–272CrossRefPubMed
46.
Osterbye T, Jorgensen KH, Fredman P et al (2001) Sulfatide promotes the folding of proinsulin, preserves insulin crystals, and mediates its monomerization. Glycobiology 11:473–479CrossRefPubMed
47.
Wright AD, Dodson PM (2011) Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies. Eye (Lond) 25:843–849CrossRef
48.
Berdyshev EV, Gorshkova I, Skobeleva A et al (2009) FTY720 inhibits ceramide synthases and up-regulates dihydrosphingosine 1-phosphate formation in human lung endothelial cells. J Biol Chem 284:5467–5477CrossRefPubMedPubMedCentral
49.
Yang Z, Chen M, Fialkow LB et al (2003) The immune modulator FYT720 prevents autoimmune diabetes in nonobese diabetic mice. Clin Immunol 107:30–35CrossRefPubMed
50.
Roep BO (2003) The role of T-cells in the pathogenesis of type 1 diabetes: from cause to cure. Diabetologia 46:305–321CrossRefPubMed
Metadata
Title
Abnormal islet sphingolipid metabolism in type 1 diabetes
Authors
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
Publication date
01-07-2018
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 7/2018
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-018-4614-2

Other articles of this Issue 7/2018

Diabetologia 7/2018 Go to the issue

Article

Spousal cardiometabolic risk factors and incidence of type 2 diabetes: a prospective analysis from the English Longitudinal Study of Ageing

Article

SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients

Review

Diabetes in the older patient: heterogeneity requires individualisation of therapeutic strategies

Up Front

Up front

Commentary

Spouses, social networks and other upstream determinants of type 2 diabetes mellitus

Short Communication

Empagliflozin in women with type 2 diabetes and cardiovascular disease – an analysis of EMPA-REG OUTCOME®
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits