Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis

Kerstin Griess, Michael Rieck, Nadine Müller, Gergely Karsai, Sonja Hartwig, Angela Pelligra, Robert Hardt, Caroline Schlegel, Jennifer Kuboth, Celina Uhlemeyer, Sandra Trenkamp, Kay Jeruschke, Jürgen Weiss, Leon Peifer-Weiss, Weiwei Xu, Sandra Cames, Xiaoyan Yi, Miriam Cnop, Mathias Beller, Holger StarkArun Kumar Kondadi, Andreas S. Reichert, Daniel Markgraf, Marianne Wammers, Dieter Häussinger, Oliver Kuss, Stefan Lehr, Decio Eizirik, Heiko Lickert, Eckhard Lammert, Michael Roden, Dominic Winter, Hadi Al-Hasani, Doris Höglinger, Thorsten Hornemann, Jens C. Brüning, Bengt Frederik Belgardt

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)20-29
Number of pages10
JournalNature Cell Biology
Volume25
Issue number1
DOIs
StatePublished - Jan 2023

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