| First Author | Griess K | Year | 2023 |
| Journal | Nat Cell Biol | Volume | 25 |
| Issue | 1 | Pages | 20-29 |
| PubMed ID | 36543979 | Mgi Jnum | J:352483 |
| Mgi Id | MGI:7520946 | Doi | 10.1038/s41556-022-01027-2 |
| Citation | Griess K, et al. (2023) Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis. Nat Cell Biol 25(1):20-29 |
| abstractText | 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. |
