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

doi:10.1016/j.celrep.2017.08.093

Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

Cell Rep. 2017 Sep 26;20(13):3135-3148. doi: 10.1016/j.celrep.2017.08.093.

Authors

Julie Adam¹, Reshma Ramracheya², Margarita V Chibalina², Nicola Ternette³, Alexander Hamilton², Andrei I Tarasov², Quan Zhang², Eduardo Rebelato⁴, Nils J G Rorsman², Rafael Martín-Del-Río⁵, Amy Lewis⁶, Gizem Özkan⁷, Hyun Woong Do², Peter Spégel⁸, Kaori Saitoh⁹, Keiko Kato⁹, Kaori Igarashi⁹, Benedikt M Kessler¹⁰, Christopher W Pugh¹¹, Jorge Tamarit-Rodriguez¹², Hindrik Mulder¹³, Anne Clark², Norma Frizzell¹⁴, Tomoyoshi Soga⁹, Frances M Ashcroft¹⁵, Andrew Silver⁶, Patrick J Pollard¹⁶, Patrik Rorsman¹⁷

Affiliations

¹ 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. Electronic address: julie.adam@ndm.ox.ac.uk.
² Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK.
³ The Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
⁴ Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK; Department of Biophysics, Federal University of Sao Paulo, Sao Paulo 04023-062, Brazil.
⁵ Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Ramón y Cajal Hospital, Madrid, Spain.
⁶ 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.
⁷ Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK.
⁸ Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, 221 00 Lund, Sweden.
⁹ Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Tsuruoka, Yamagata 997-0052, Japan.
¹⁰ Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
¹¹ 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.
¹² Biochemistry Department, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain.
¹³ Lund University Diabetes Centre, Unit of Molecular Metabolism, Clinical Research Centre, Malmo University Hospital, 20502 Malmo, Sweden.
¹⁴ Department of Pharmacology, Physiology & Neuroscience, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
¹⁵ Department of Physiology, Anatomy and Genetics, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
¹⁶ Nuffield Department of Medicine, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK; Department of Physiology, Institute of Neuroscience and Physiology, University of Göteborg, 405 30 Göteborg, Sweden.
¹⁷ Radcliffe Department of Medicine, OCDEM, Churchill Hospital, University of Oxford, Oxford OX3 7LE, UK; Department of Physiology, Institute of Neuroscience and Physiology, University of Göteborg, 405 30 Göteborg, Sweden. Electronic address: patrik.rorsman@hmc.ox.ac.uk.

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: diabetes; fumarate; fumarate hydratase; glucose metabolism; hyperglycemia; insulin; mouse model; pH; succination; β cell.

MeSH terms

Animals
Diabetes Mellitus, Type 2 / genetics*
Diabetes Mellitus, Type 2 / metabolism
Fumarate Hydratase / deficiency*
Humans
Insulin-Secreting Cells / metabolism*
Islets of Langerhans / metabolism*
Mice

Substances

Fumarate Hydratase

Abstract

MeSH terms

Substances

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