Fumarate Hydratase Deletion in Pancreatic β 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 β cells (Fh1βKO mice) appear normal for 6–8 weeks but then develop progressive glucose intolerance and diabetes. Glucose tolerance is rescued by expre...
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| Format: | Article |
| Language: | English |
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Elsevier
2017-09-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124717312354 |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes Cell Reports fumarate hydratase β cell diabetes fumarate glucose metabolism hyperglycemia insulin mouse model pH succination |
| author_facet |
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 |
| author_sort |
Julie Adam |
| title |
Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes |
| title_short |
Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes |
| title_full |
Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes |
| title_fullStr |
Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes |
| title_full_unstemmed |
Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes |
| title_sort |
fumarate hydratase deletion in pancreatic β cells leads to progressive diabetes |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2017-09-01 |
| description |
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. |
| topic |
fumarate hydratase β cell diabetes fumarate glucose metabolism hyperglycemia insulin mouse model pH succination |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124717312354 |
| work_keys_str_mv |
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doaj-05d52d7c48f340449106e32e0dd4ebf72020-11-25T02:09:25ZengElsevierCell Reports2211-12472017-09-0120133135314810.1016/j.celrep.2017.08.093Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive DiabetesJulie Adam0Reshma Ramracheya1Margarita V. Chibalina2Nicola Ternette3Alexander Hamilton4Andrei I. Tarasov5Quan Zhang6Eduardo Rebelato7Nils J.G. Rorsman8Rafael Martín-del-Río9Amy Lewis10Gizem Özkan11Hyun Woong Do12Peter Spégel13Kaori Saitoh14Keiko Kato15Kaori Igarashi16Benedikt M. Kessler17Christopher W. Pugh18Jorge Tamarit-Rodriguez19Hindrik Mulder20Anne Clark21Norma Frizzell22Tomoyoshi Soga23Frances M. Ashcroft24Andrew Silver25Patrick J. Pollard26Patrik Rorsman27Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKThe Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKInstituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ramón y Cajal Hospital, Madrid, SpainCentre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UKNuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKCentre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 221 00 Lund, SwedenInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanTarget Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UKNuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKBiochemistry Department, School of Medicine, Complutense University of Madrid, 28040 Madrid, SpainLund University Diabetes Centre, Unit of Molecular Metabolism, Clinical Research Centre, Malmo University Hospital, 20502 Malmo, SwedenRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKDepartment of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208, USAInstitute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, JapanDepartment of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UKCentre for Genomics and Child Health, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UKNuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UKRadcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UKWe 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.http://www.sciencedirect.com/science/article/pii/S2211124717312354fumarate hydrataseβ celldiabetesfumarateglucose metabolismhyperglycemiainsulinmouse modelpHsuccination |