Abstract

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 TCA cycle and electron transport chain (ETC). Using human diabetic samples 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 (DeltaPsim) 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 mTORC1-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 mTORC1 inhibition as a potential mitigation strategy.

View details for DOI 10.2337/db21-0834

View details for PubMedID 35472723