Cell Reports (Sep 2017)
Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes
- Julie Adam,
- Reshma Ramracheya,
- Margarita V. Chibalina,
- Nicola Ternette,
- Alexander Hamilton,
- Andrei I. Tarasov,
- Quan Zhang,
- Eduardo Rebelato,
- Nils J.G. Rorsman,
- Rafael Martín-del-Río,
- Amy Lewis,
- Gizem Özkan,
- Hyun Woong Do,
- Peter Spégel,
- Kaori Saitoh,
- Keiko Kato,
- Kaori Igarashi,
- Benedikt M. Kessler,
- Christopher W. Pugh,
- Jorge Tamarit-Rodriguez,
- Hindrik Mulder,
- Anne Clark,
- Norma Frizzell,
- Tomoyoshi Soga,
- Frances M. Ashcroft,
- Andrew Silver,
- Patrick J. Pollard,
- Patrik Rorsman
Affiliations
- Julie Adam
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Reshma Ramracheya
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Margarita V. Chibalina
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Nicola Ternette
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
- Alexander Hamilton
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Andrei I. Tarasov
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Quan Zhang
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Eduardo Rebelato
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Nils J.G. Rorsman
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Rafael Martín-del-Río
- Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ramón y Cajal Hospital, Madrid, Spain
- Amy Lewis
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
- Gizem Özkan
- Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
- Hyun Woong Do
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Peter Spégel
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 221 00 Lund, Sweden
- Kaori Saitoh
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
- Keiko Kato
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
- Kaori Igarashi
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
- Benedikt M. Kessler
- Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
- Christopher W. Pugh
- Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
- Jorge Tamarit-Rodriguez
- Biochemistry Department, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Hindrik Mulder
- Lund University Diabetes Centre, Unit of Molecular Metabolism, Clinical Research Centre, Malmo University Hospital, 20502 Malmo, Sweden
- Anne Clark
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- Norma Frizzell
- Department of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
- Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan
- Frances M. Ashcroft
- Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK
- Andrew Silver
- Centre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK
- Patrick J. Pollard
- Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK
- Patrik Rorsman
- Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK
- DOI
- https://doi.org/10.1016/j.celrep.2017.08.093
- Journal volume & issue
-
Vol. 20,
no. 13
pp. 3135 – 3148
Abstract
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 [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 Fh1βKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.
Keywords
- fumarate hydratase
- β cell
- diabetes
- fumarate
- glucose metabolism
- hyperglycemia
- insulin
- mouse model
- pH
- succination
