| First Author | Lee S | Year | 2022 |
| Journal | Diabetes | Volume | 71 |
| Issue | 7 | Pages | 1439-1453 |
| PubMed ID | 35472723 | Mgi Jnum | J:326592 |
| Mgi Id | MGI:7314377 | Doi | 10.2337/db21-0834 |
| Citation | Lee S, et al. (2022) beta-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes. Diabetes 71(7):1439-1453 |
| abstractText | Mitochondrial dysfunction plays a central role in type 2 diabetes (T2D); however, the pathogenic mechanisms in pancreatic beta-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is a key mitochondrial enzyme with dual functions in the tricarboxylic acid cycle and electron transport chain. Using samples from human with diabetes and a mouse model of beta-cell-specific SDH ablation (SDHBbetaKO), we define SDH deficiency as a driver of mitochondrial dysfunction in beta-cell failure and insulinopenic diabetes. beta-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential collapse, thereby compromising glucose-stimulated ATP production, insulin secretion, and beta-cell growth. Mechanistically, metabolomic and transcriptomic studies reveal that the loss of SDH causes excess succinate accumulation, which inappropriately activates mammalian target of rapamycin (mTOR) complex 1-regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, which mirror diabetes-associated human beta-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive beta-cell failure of diabetes and identify mTOR complex 1 inhibition as a potential mitigation strategy. |
