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

School of Biomedical Sciences

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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 (in print/issue) - 26 Sept 2017

Keywords

fumarate hydratase
β cell
diabetes
fumarate
glucose metabolism
hyperglycemia
insulin
mouse model
pH
succination

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.08.093Licence: CC BY

Extended Final Published versionFinal published version, 11.3 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

@article{c6801f393dac4827a9edd92c705273f6,

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 = "fumarate hydratase, β cell, diabetes, fumarate, glucose metabolism, hyperglycemia, insulin, mouse model, pH, succination",

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",

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 = "Elsevier",

number = "13",

}

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 - fumarate hydratase

KW - β cell

KW - diabetes

KW - fumarate

KW - glucose metabolism

KW - hyperglycemia

KW - insulin

KW - mouse model

KW - pH

KW - succination

UR - https://linkinghub.elsevier.com/retrieve/pii/S2211124717312354

UR - https://www.sciencedirect.com/science/article/pii/S2211124717312354

UR - https://pure.ulster.ac.uk/en/publications/fumarate-hydratase-deletion-in-pancreatic-%CE%B2-cells-leads-to-progre

U2 - 10.1016/j.celrep.2017.08.093

DO - 10.1016/j.celrep.2017.08.093

M3 - Article

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

Abstract

Keywords

UN SDGs

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