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-RodriguezHindrik Mulder, Anne Clark, Norma Frizzell, Tomoyoshi Soga, Frances M. Ashcroft, Andrew Silver, Patrick J. Pollard, Patrik Rorsman

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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.
Original languageEnglish
Pages (from-to)3135-3148
Number of pages14
JournalCell Reports
Volume20
Issue number13
DOIs
Publication statusPublished - 26 Sep 2017

Keywords

  • fumarate hydratase
  • β cell
  • diabetes
  • fumarate
  • glucose metabolism
  • hyperglycemia
  • insulin
  • mouse model
  • pH
  • succination

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