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

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posted on 26.04.2022, 21:27 by Sooyeon Lee, Haixia Xu, Aidan Van Vleck, Alex M. Mawla, Albert Mao Li, Jiangbin Ye, Mark O. Huising, Justin P. Annes

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


The authors would like to acknowledge the Vanderbilt Islet Procurement and Analysis Core for the islet perifusion studies (NIH P30 DK020593) and the Northwest Metabolomics Research Center for performing metabolomics analysis. Human tissue sections were provided by the Network for Pancreatic Organ Donors with diabetes (nPOD), a collaborative research project with JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at We also thank Yang Li for assistance with LC/MS. This work was supported by National Institutes of Health (NIH) Grants (R01 DK101530, R01 DK119955 and P30 DK116074) and the Juvenile Diabetes Research Foundation (JDRF 2-SRA-2019-800-S-B) to JPA. SL received funding from Endocrinology Training grant (T32DK007217) and Stanford Child Health Research Institute (UL1TR001085). HX was supported by an NIH Grant (R01 EB025867) to JPA. MOH. received support from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK-110276), the Juvenile Diabetes Research Foundation (2-SRA-2019-700-SB) and the American Diabetes Association (1-19-IBS-078). A.M.L and J.Y. received support from the American Cancer Society (RSG-20-036-01).