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.

中文翻译：

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β-细胞琥珀酸脱氢酶缺乏会引发代谢功能障碍和胰岛素缺乏性糖尿病。


线粒体功能障碍在 2 型糖尿病 (T2D) 中发挥着核心作用；然而，胰腺β细胞的致病机制尚未完全阐明。琥珀酸脱氢酶（SDH）是一种关键的线粒体酶，在三羧酸循环和电子传递链中具有双重功能。使用糖尿病患者样本和 β 细胞特异性 SDH 消融 (SDHBβKO) 小鼠模型，我们将 SDH 缺乏定义为 β 细胞衰竭和胰岛素缺乏性糖尿病中线粒体功能障碍的驱动因素。 β-细胞 SDH 缺乏会损害葡萄糖诱导的呼吸氧化磷酸化和线粒体膜电位崩溃，从而损害葡萄糖刺激的 ATP 产生、胰岛素分泌和 β 细胞生长。从机制上来说，代谢组学和转录组学研究表明，SDH 的缺失会导致琥珀酸过量积累，从而不适当地激活哺乳动物雷帕霉素靶点 (mTOR) 复合物 1 调节的代谢合成代谢，包括增加 SREBP 调节的脂质合成。这些改变反映了糖尿病相关的人类 β 细胞功能障碍，可通过雷帕霉素的急性 mTOR 抑制部分逆转。我们提出 SDH 缺乏是导致糖尿病进行性 β 细胞衰竭的一个机制，并将 mTOR 复合物 1 抑制确定为潜在的缓解策略。