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-Rodriguez; Hindrik Mulder; Anne Clark; Norma Frizzell; Tomoyoshi Soga; Frances M Ashcroft; Andrew Silver; Patrick J Pollard; Patrik Rorsman

doi:10.1016/j.celrep.2017.08.093

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 language	English
Pages (from-to)	3135-3148
Number of pages	14
Journal	Cell Reports
Volume	20
Issue number	13
DOIs	https://doi.org/10.1016/j.celrep.2017.08.093
Publication status	Published - 26 Sept 2017

Keywords

Animals
Diabetes Mellitus, Type 2/genetics
Fumarate Hydratase/deficiency
Humans
Insulin-Secreting Cells/metabolism
Islets of Langerhans/metabolism
Mice

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1-s2.0-S2211124717312354-mainFinal published version, 4.1 MBLicence: CC BY

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Adam, J., Ramracheya, R., Chibalina, M. V., Ternette, N., Hamilton, A., Tarasov, A. I., Zhang, Q., Rebelato, E., Rorsman, N. J. G., Martín-Del-Río, R., Lewis, A., Özkan, G., Do, H. W., Spégel, P., Saitoh, K., Kato, K., Igarashi, K., Kessler, B. M., Pugh, C. W., ... Rorsman, P. (2017). Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes. Cell Reports, 20(13), 3135-3148. https://doi.org/10.1016/j.celrep.2017.08.093

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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.",

keywords = "Animals, Diabetes Mellitus, Type 2/genetics, Fumarate Hydratase/deficiency, Humans, Insulin-Secreting Cells/metabolism, Islets of Langerhans/metabolism, Mice",

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 = "{\textcopyright} 2017 The Author(s).",

year = "2017",

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doi = "10.1016/j.celrep.2017.08.093",

language = "English",

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Adam, J, Ramracheya, R, Chibalina, MV, Ternette, N, Hamilton, A, Tarasov, AI, Zhang, Q, Rebelato, E, Rorsman, NJG, Martín-Del-Río, R, Lewis, A, Özkan, G, Do, HW, Spégel, P, Saitoh, K, Kato, K, Igarashi, K, Kessler, BM, Pugh, CW, Tamarit-Rodriguez, J, Mulder, H, Clark, A, Frizzell, N, Soga, T, Ashcroft, FM, Silver, A, Pollard, PJ & Rorsman, P 2017, 'Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes', Cell Reports, vol. 20, no. 13, pp. 3135-3148. https://doi.org/10.1016/j.celrep.2017.08.093

TY - JOUR

T1 - Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

AU - Adam, Julie

AU - Ramracheya, Reshma

AU - Chibalina, Margarita V

AU - Ternette, Nicola

AU - Hamilton, Alexander

AU - Tarasov, Andrei I

AU - Zhang, Quan

AU - Rebelato, Eduardo

AU - Rorsman, Nils J G

AU - Martín-Del-Río, Rafael

AU - Lewis, Amy

AU - Özkan, Gizem

AU - Do, Hyun Woong

AU - Spégel, Peter

AU - Saitoh, Kaori

AU - Kato, Keiko

AU - Igarashi, Kaori

AU - Kessler, Benedikt M

AU - Pugh, Christopher W

AU - Tamarit-Rodriguez, Jorge

AU - Mulder, Hindrik

AU - Clark, Anne

AU - Frizzell, Norma

AU - Soga, Tomoyoshi

AU - Ashcroft, Frances M

AU - Silver, Andrew

AU - Pollard, Patrick J

AU - Rorsman, Patrik

PY - 2017/9/26

Y1 - 2017/9/26

N2 - 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.

AB - 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.

KW - Animals

KW - Diabetes Mellitus, Type 2/genetics

KW - Fumarate Hydratase/deficiency

KW - Humans

KW - Insulin-Secreting Cells/metabolism

KW - Islets of Langerhans/metabolism

KW - Mice

U2 - 10.1016/j.celrep.2017.08.093

DO - 10.1016/j.celrep.2017.08.093

M3 - Article

C2 - 28954230

SN - 2211-1247

VL - 20

SP - 3135

EP - 3148

JO - Cell Reports

JF - Cell Reports

IS - 13

ER -

Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

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