Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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. Adam et al. have shown that progressive diabetes develops if fumarate hydratase is deleted in mouse pancreatic β cells. Such β cells exhibit elevated fumarate and protein succination and show progressively reduced ATP production and insulin secretion. The depleted insulin response to glucose recovers when diabetic islets are cultured in reduced glucose.

Detaljer

Författare
  • Julie Adam
  • Reshma Ramracheya
  • Margarita V. Chibalina
  • Nicola Ternette
  • Andrei I. Tarasov
  • Quan Zhang
  • Eduardo Rebelato
  • Nils J.G. Rorsman
  • Rafael Martín-del-Río
  • Amy Lewis
  • Gizem Özkan
  • Hyun Woong Do
  • Kaori Saitoh
  • Keiko Kato
  • Kaori Igarashi
  • Benedikt M. Kessler
  • Christopher W. Pugh
  • Jorge Tamarit-Rodriguez
  • Anne Clark
  • Norma Frizzell
  • Tomoyoshi Soga
  • Frances M. Ashcroft
  • Andrew Silver
  • Patrick J. Pollard
  • Patrik Rorsman
Enheter & grupper
Externa organisationer
  • University of Oxford
  • Escola Paulista de Medicina
  • Hospital Ramón Y Cajal
  • Queen Mary University
  • Keio University
  • Complutense University of Madrid
  • Göteborgs universitet
  • University of South Carolina
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Endokrinologi och diabetes

Nyckelord

Originalspråkengelska
Sidor (från-till)3135-3148
Antal sidor14
TidskriftCell Reports
Volym20
Utgivningsnummer13
StatusPublished - 2017 sep 26
PublikationskategoriForskning
Peer review utfördJa