Griess, Kerstin ORCID: 0000-0002-6672-2394, Rieck, Michael, Muller, Nadine ORCID: 0000-0002-4760-6144, Karsai, Gergely ORCID: 0000-0002-6840-682X, Hartwig, Sonja ORCID: 0000-0002-5225-6804, Pelligra, Angela, Hardt, Robert ORCID: 0000-0003-2939-7657, Schlegel, Caroline, Kuboth, Jennifer, Uhlemeyer, Celina, Trenkamp, Sandra, Jeruschke, Kay, Weiss, Jurgen, Peifer-Weiss, Leon, Xu, Weiwei, Cames, Sandra, Yi, Xiaoyan, Cnop, Miriam, Beller, Mathias, Stark, Holger, Kondadi, Arun Kumar, Reichert, Andreas S., Markgraf, Daniel, Wammers, Marianne, Haeussinger, Dieter, Kuss, Oliver, Lehr, Stefan, Eizirik, Decio, Lickert, Heiko, Lammert, Eckhard, Roden, Michael, Winter, Dominic ORCID: 0000-0001-6788-6641, Al-Hasani, Hadi, Hoeglinger, Doris, Hornemann, Thorsten, Bruning, Jens C. and Belgardt, Bengt-Frederik ORCID: 0000-0003-4537-9002 . Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis. Nat. Cell Biol.. BERLIN: NATURE PORTFOLIO. ISSN 1476-4679

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Abstract

Impaired proinsulin-to-insulin processing in pancreatic beta-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 beta-cell function and demise is unclear. Here we define the lipid signature of T2D-associated beta-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. beta-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 beta-cell function and T2D-associated beta-cell failure.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Griess, KerstinUNSPECIFIEDorcid.org/0000-0002-6672-2394UNSPECIFIED
Rieck, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muller, NadineUNSPECIFIEDorcid.org/0000-0002-4760-6144UNSPECIFIED
Karsai, GergelyUNSPECIFIEDorcid.org/0000-0002-6840-682XUNSPECIFIED
Hartwig, SonjaUNSPECIFIEDorcid.org/0000-0002-5225-6804UNSPECIFIED
Pelligra, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hardt, RobertUNSPECIFIEDorcid.org/0000-0003-2939-7657UNSPECIFIED
Schlegel, CarolineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuboth, JenniferUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Uhlemeyer, CelinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trenkamp, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jeruschke, KayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weiss, JurgenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer-Weiss, LeonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Xu, WeiweiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cames, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yi, XiaoyanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cnop, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Beller, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stark, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kondadi, Arun KumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reichert, Andreas S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Markgraf, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wammers, MarianneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haeussinger, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuss, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lehr, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eizirik, DecioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lickert, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lammert, EckhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roden, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Winter, DominicUNSPECIFIEDorcid.org/0000-0001-6788-6641UNSPECIFIED
Al-Hasani, HadiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoeglinger, DorisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hornemann, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruning, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Belgardt, Bengt-FrederikUNSPECIFIEDorcid.org/0000-0003-4537-9002UNSPECIFIED
URN: urn:nbn:de:hbz:38-693749
DOI: 10.1038/s41556-022-01027-2
Journal or Publication Title: Nat. Cell Biol.
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 1476-4679
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
BETA-CELL; COMPUTATIONAL PLATFORM; CERAMIDE; INSULIN; OBESITY; ISLETS; SECRETION; SIGNATURE; OXIDATION; BIOLOGYMultiple languages
Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69374

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