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

研究成果: Article査読

37 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)3135-3148
ページ数14
ジャーナルCell Reports
20
13
DOI
出版ステータスPublished - 2017 9月 26

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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