| First Author | Lin H | Year | 2024 |
| Journal | Nat Commun | Volume | 15 |
| Issue | 1 | Pages | 334 |
| PubMed ID | 38184650 | Mgi Jnum | J:346178 |
| Mgi Id | MGI:7575182 | Doi | 10.1038/s41467-023-44589-x |
| Citation | Lin H, et al. (2024) A role and mechanism for redox sensing by SENP1 in beta-cell responses to high fat feeding. Nat Commun 15(1):334 |
| abstractText | Pancreatic beta-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. Here we show, in beta-cells from overweight humans without diabetes and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca(2+) influx. RNA-seq of sorted beta-cells suggests altered metabolic pathways early following high fat diet, where we find increased basal oxygen consumption and proton leak, but a more reduced cytosolic redox state. Increased beta-cell exocytosis after 2-day high fat diet is dependent on this reduced intracellular redox state and requires the sentrin-specific SUMO-protease-1. Mice with either pancreas- or beta-cell-specific deletion of this fail to up-regulate exocytosis and become rapidly glucose intolerant after 2-day high fat diet. Mechanistically, redox-sensing by the SUMO-protease requires a thiol group at C535 which together with Zn(+)-binding suppresses basal protease activity and unrestrained beta-cell exocytosis, and increases enzyme sensitivity to regulation by redox signals. |
