Fumarate Hydratase Deletion in Pancreatic beta Cells Leads to Progressive Diabetes
We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic beta cells (Fh1 beta KO 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 Hif1 alpha or Nrf2. Progressive hyperglycemia in Fh1bKO mice led to dysregulated metabolism in b cells, a decrease in glucose-induced ATP production, electrical activity, cytoplasmic [Ca2+](i) 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 Fh1bKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D. ; Wellcome Trust ; Yamagata Prefectural Government ; City of Tsuruoka ; Swedish Research Council ; Knut and Alice Wallenbergs Stiftelse ; FAPESP ; Spanish Ministry of Science and Technology ; Royal Society/Wolfson merit award ; ERC ; Diabetes UK ; Univ Oxford, Churchill Hosp, Radcliffe Dept Med, OCDEM, Oxford OX3 7LE, England ; Univ Oxford, Nuffield Dept Med, Henry Wellcome Bldg Mol Physiol, Oxford OX3 7BN, England ; Univ Oxford, NDMRB, Nuffield Dept Med, Oxford OX3 7FZ, England ; Univ Oxford, Nuffield Dept Med, Jenner Inst, Oxford OX3 7FZ, England ; Univ Fed Sao Paulo, Dept Biophys, BR-04023062 Sao Paulo, Brazil ; Ramon & Cajal Hosp, Inst Ramon & Cajal Invest Sanitaria IRYCIS, Madrid, Spain ; Queen Mary Univ London, Barts & London Sch Med & Dent, Blizard Inst, Ctr Genom & Child Hlth, London E1 2AT, England ; Lund Univ, Dept Chem, Ctr Anal & Synth, Box 124, S-22100 Lund, Sweden ; Keio Univ, Inst Adv Biosci, 246-2 Mizukami, Tsuruoka, Yamagata 9970052, Japan ; Univ Oxford, Nuffield Dept Med, Target Discovery Inst, Oxford OX3 7FZ, England ; Univ Complutense Madrid, Sch Med, Biochem Dept, E-28040 Madrid, Spain ; Lund Univ, Malmo Univ Hosp, Clin Res Ctr, Diabet Ctr,Unit Mol Metab, S-20502 Malmo, Sweden ; Univ South Carolina, Sch Med, Dept Pharmacol Physiol & Neurosci, Columbia, SC 29208 USA ; Univ Oxford, Dept Physiol Anat & Genet, Parks Rd, Oxford OX1 3PT, England ; Univ Gothenburg, Dept Physiol, Inst Neurosci & Physiol, S-40530 Gothenburg, Sweden ; Univ Fed Sao Paulo, Dept Biophys, BR-04023062 Sao Paulo, Brazil ; Web of Science
