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Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

Adam, Julie; Ramracheya, Reshma; Chibalina, Margarita V.; Ternette, Nicola; Hamilton, Alexander; Tarasov, Andrei I.; Zhang, Quan; Rebelato, Eduardo; Rorsman, Nils J.G. and Martín-del-Río, Rafael, et al. (2017) In Cell Reports 20(13). p.3135-3148
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... (More)

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.

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@article{d7f23e2d-98f6-4456-9555-3c33d187b5a6,
  abstract     = {<p>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 [Ca<sup>2+</sup>]<sub>i</sub> 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.</p>},
  author       = {Adam, Julie and Ramracheya, Reshma and Chibalina, Margarita V. and Ternette, Nicola and Hamilton, Alexander and Tarasov, Andrei I. and Zhang, Quan and Rebelato, Eduardo and Rorsman, Nils J.G. and Martín-del-Río, Rafael and Lewis, Amy and Özkan, Gizem and Do, Hyun Woong and Spégel, Peter and Saitoh, Kaori and Kato, Keiko and Igarashi, Kaori and Kessler, Benedikt M. and Pugh, Christopher W. and Tamarit-Rodriguez, Jorge and Mulder, Hindrik and Clark, Anne and Frizzell, Norma and Soga, Tomoyoshi and Ashcroft, Frances M. and Silver, Andrew and Pollard, Patrick J. and Rorsman, Patrik},
  issn         = {2211-1247},
  keyword      = {diabetes,fumarate,fumarate hydratase,glucose metabolism,hyperglycemia,insulin,mouse model,pH,succination,β cell},
  language     = {eng},
  month        = {09},
  number       = {13},
  pages        = {3135--3148},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes},
  url          = {http://dx.doi.org/10.1016/j.celrep.2017.08.093},
  volume       = {20},
  year         = {2017},
}