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β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes.
- Source :
-
Diabetes [Diabetes] 2022 Jul 01; Vol. 71 (7), pp. 1439-1453. - Publication Year :
- 2022
-
Abstract
- Mitochondrial dysfunction plays a central role in type 2 diabetes (T2D); however, the pathogenic mechanisms in pancreatic β-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 β-cell-specific SDH ablation (SDHBβKO), we define SDH deficiency as a driver of mitochondrial dysfunction in β-cell failure and insulinopenic diabetes. β-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential collapse, thereby compromising glucose-stimulated ATP production, insulin secretion, and β-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 β-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive β-cell failure of diabetes and identify mTOR complex 1 inhibition as a potential mitigation strategy.<br /> (© 2022 by the American Diabetes Association.)
- Subjects :
- Animals
Electron Transport Complex II deficiency
Glucose metabolism
Insulin-Secreting Cells
Metabolism, Inborn Errors
Mice
Mitochondrial Diseases
TOR Serine-Threonine Kinases metabolism
Diabetes Mellitus, Type 2 metabolism
Succinate Dehydrogenase deficiency
Succinate Dehydrogenase genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1939-327X
- Volume :
- 71
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 35472723
- Full Text :
- https://doi.org/10.2337/db21-0834