@article{fa922b4e13a0465fb9fa079c9edb11aa,
title = "Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes",
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.",
keywords = "diabetes, fumarate, fumarate hydratase, glucose metabolism, hyperglycemia, insulin, mouse model, pH, succination, β cell",
author = "Julie Adam and Reshma Ramracheya and Chibalina, {Margarita V.} and Nicola Ternette and Alexander Hamilton and Tarasov, {Andrei I.} and Quan Zhang and Eduardo Rebelato and Rorsman, {Nils J.G.} and Rafael Mart{\'i}n-del-R{\'i}o and Amy Lewis and Gizem {\"O}zkan and Do, {Hyun Woong} and Peter Sp{\'e}gel and Kaori Saitoh and Keiko Kato and Kaori Igarashi and Kessler, {Benedikt M.} and Pugh, {Christopher W.} and Jorge Tamarit-Rodriguez and Hindrik Mulder and Anne Clark and Norma Frizzell and Tomoyoshi Soga and Ashcroft, {Frances M.} and Andrew Silver and Pollard, {Patrick J.} and Patrik Rorsman",
note = "Funding Information: We thank David Wiggins for technical support, staff at the Oxford University Biomedical Services facilities for taking care of the mice, and Professor P.R.V. Johnson and his team for provision of human pancreatic islets. We are grateful to Randall Johnson and Pedro Herrera for providing Hif1α and Rip-Cre mice, respectively, and Ralph Deberardinis for critical evaluation of the metabolomics analyses. We thank the Wellcome Trust for core infrastructure support to the Wellcome Trust Centre for Human Genetics, Oxford ( 090532/Z/09/Z ), a Wellcome Trust Senior Investigator Award ( 095531/Z/11/Z ) to P.R., and grants to F.M.A. ( 884655 and 089795 ). T.S. is supported by a Grant-in-Aid for Scientific Research on Innovative Areas, Japan ( 22134007 ) and the Yamagata Prefectural Government and City of Tsuruoka ; H.M., P.S., and P.R. are supported by the Swedish Research Council ; P.R. is supported by the Knut and Alice Wallenbergs Stiftelse (Wallenberg Scholars) ; and E.R. is supported by FAPESP . R.M.d.R. and J.T.-R. were partially supported by a grant from the Spanish Ministry of Science and Technology : SAF2009/1267 . F.M.A. holds a Royal Society/Wolfson merit award and an ERC Advanced Investigatorship ( 322620 ). A.L. is a Barts and The London Charity post-doctoral fellow. R.R. and Q.Z. are Diabetes UK RD Lawrence fellows, and A.H. holds a PhD studentship funded by Diabetes UK. Publisher Copyright: {\textcopyright} 2017 The Author(s)",
year = "2017",
month = sep,
day = "26",
doi = "10.1016/j.celrep.2017.08.093",
language = "English",
volume = "20",
pages = "3135--3148",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "13",
}
