β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes

• DOI: 10.2337/db21-0834
• Publication Date: 2022-04-26T21:03:35Z
• Authors: Sooyeon Lee; Haixia Xu; Aidan Van Vleck; Alex M. Mawla; Albert Mao Li; Jiangbin Ye; Mark O. Huising; Justin P. Annes
• Keywords: 0301 basic medicine; Biomedical and clinical sciences; Mitochondrial Diseases; 610; 612; Medical and Health Sciences; Endocrinology & Metabolism; Mice; 03 medical and health sciences; Rare Diseases; Insulin-Secreting Cells; Diabetes Mellitus; 2.1 Biological and endogenous factors; Animals; Metabolic and endocrine; Nutrition; 0303 health sciences; Biomedical and Clinical Sciences; Inborn Errors; Electron Transport Complex II; TOR Serine-Threonine Kinases; Diabetes; Succinate Dehydrogenase; Metabolism; Glucose; Islet Studies; Diabetes Mellitus, Type 2; Type 2; Metabolism, Inborn Errors

Mitochondrial dysfunction plays a central role in type 2 diabetes (T2D); however, the pathogenic mechanisms pancreatic β-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is key mitochondrial enzyme with dual functions tricarboxylic acid cycle and electron transport chain. Using samples from human mouse model of β-cell–specific SDH ablation (SDHBβKO), we define deficiency as driver β-cell failure insulinopenic diabetes. β-Cell impairs glucose-induced respiratory oxidative phosphorylation membrane potential collapse, thereby compromising glucose-stimulated ATP production, insulin secretion, growth. Mechanistically, metabolomic transcriptomic studies reveal that loss causes excess succinate accumulation, which inappropriately activates mammalian target rapamycin (mTOR) complex 1–regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, mirror diabetes-associated dysfunction, partially reversed by acute mTOR inhibition rapamycin. We propose contributing mechanism to progressive identify 1 mitigation strategy.