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Griess, K.* ; Rieck, M.* ; Müller, N.* ; Karsai, G.* ; Hartwig, S.* ; Pelligra, A.* ; Hardt, R.* ; Schlegel, C.* ; Kuboth, J.* ; Uhlemeyer, C.* ; Trenkamp, S.* ; Jeruschke, K.* ; Weiss, J.* ; Peifer-Weiss, L.* ; Xu, W. ; Cames, S.* ; Yi, X.* ; Cnop, M.* ; Beller, M.* ; Stark, H.* ; Kondadi, A.K.* ; Reichert, A.S.* ; Markgraf, D.* ; Wammers, M.* ; Häussinger, D.* ; Kuss, O.* ; Lerch, S.* ; Eizirik, D.L.* ; Lickert, H. ; Lammert, E.* ; Roden, M.* ; Winter, D.* ; Al-Hasani, H.* ; Höglinger, D.* ; Hornemann, T.* ; Brüning, J.C.* ; Belgardt, B.F.*

Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis.

Nat. Cell Biol. 25, 20–29 (2023)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs. 1,2), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs. 3–8); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL–protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum–Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Beta-cell; Computational Platform; Ceramide; Insulin; Obesity; Islets; Secretion; Signature; Oxidation; Biology
Sprache englisch
Veröffentlichungsjahr 2023
Prepublished im Jahr 2022
HGF-Berichtsjahr 2022
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Zeitschrift Nature Cell Biology
Quellenangaben Band: 25, Heft: 1, Seiten: 20–29 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Heidelberger Platz 3, Berlin, 14197, Germany
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Regeneration Research (IDR)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502300-001
Förderungen Ministry of Culture and Science of the State of North Rhine-Westfalia (MKW NRW)
German Federal Ministry of Health (BMG)
Federal Ministry for Research (BMBF)
Belgian Fonds National de la Recherche Scientifique (FNRS)
SENSE Foundation
Francophone Foundation for Diabetes Research
French Diabetes Federation
Abbott
German Diabetes Center
Merck Sharp Dohme
Novo Nordisk
European Foundation for the Study
Deutsche Forschungsgemeinschaft (DFG)
European Research Council (ERC) under the European Union
European Research Council (ERC)
Eli Lilly
DOI 10.1038/s41556-022-01027-2
WOS ID 000901870600001
WOS ID WOS:000901870600001
Scopus ID 85144505812
PubMed ID 36543979
Erfassungsdatum 2023-01-12
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