Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK; Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK; Nuffield Department of Medicine, NDMRB, University of Oxford, Oxford OX3 7FZ, UK.
Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK.
Cell Rep. 2017 Sep 26;20(13):3135-3148. doi: 10.1016/j.celrep.2017.08.093.
We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic β cells (Fh1βKO mice) appear normal for 6-8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expression of mitochondrial or cytosolic FH but not by deletion of Hif1α or Nrf2. Progressive hyperglycemia in Fh1βKO mice led to dysregulated metabolism in β cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca] elevation, and GSIS. Fh1 loss resulted in elevated intracellular fumarate, promoting succination of critical cysteines in GAPDH, GMPR, and PARK 7/DJ-1 and cytoplasmic acidification. Intracellular fumarate levels were increased in islets exposed to high glucose and in islets from human donors with type 2 diabetes (T2D). The impaired GSIS in islets from diabetic Fh1βKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.
我们探讨了克雷布斯循环酶富马酸水合酶 (FH) 在葡萄糖刺激的胰岛素分泌 (GSIS) 中的作用。胰腺β细胞中缺乏 Fh1 的小鼠 (Fh1βKO 小鼠) 在 6-8 周内看起来正常，但随后会逐渐出现葡萄糖不耐受和糖尿病。表达线粒体或细胞质 FH 可挽救葡萄糖耐量，但缺失 Hif1α 或 Nrf2 则不能。Fh1βKO 小鼠进行性高血糖导致β细胞代谢失调、葡萄糖诱导的 ATP 产生、电活动、细胞质 [Ca] 升高和 GSIS 减少。Fh1 的缺失导致细胞内富马酸水平升高，促进 GAPDH、GMPR 和 PARK 7/DJ-1 中的关键半胱氨酸琥珀酰化和细胞质酸化。在高葡萄糖暴露的胰岛和 2 型糖尿病 (T2D) 供体的胰岛中，细胞内富马酸水平升高。在正常血糖条件下培养后，糖尿病 Fh1βKO 小鼠胰岛中受损的 GSIS 得到改善。这些研究强调了 FH 和代谢失调在 T2D 中的作用。
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