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Fumarate Hydratase Deletion in Pancreatic beta Cells Leads to Progressive Diabetes

Journal article
Authors J. Adam
R. Ramracheya
M. V. Chibalina
N. Ternette
A. Hamilton
A. I. Tarasov
Q. Zhang
E. Rebelato
N. J. G. Rorsman
R. Martin-del-Rio
A. Lewis
G. Ozkan
H. W. Do
P. Spegel
K. Saitoh
K. Kato
K. Igarashi
B. M. Kessler
C. W. Pugh
J. Tamarit-Rodriguez
H. Mulder
A. Clark
N. Frizzell
T. Soga
Frances M. Ashcroft
A. Silver
Patrick Pollard
Patrik Rorsman
Published in Cell Reports
Volume 20
Issue 13
Pages 3135-3148
ISSN 2211-1247
Publication year 2017
Published at Institute of Neuroscience and Physiology, Department of Physiology
Pages 3135-3148
Language en
Links dx.doi.org/10.1016/j.celrep.2017.08...
Keywords insulin-secretion, mitochondrial stress, chemical-modification, glucose-homeostasis, metabolism, dehydrogenase, succination, biomarker, pathway, islets, Cell Biology
Subject categories Physiology

Abstract

We explored the role of the Krebs cycle enzyme fumarate hydratase (FH) in glucose-stimulated insulin secretion (GSIS). Mice lacking Fh1 in pancreatic beta cells (Fh1 beta KO 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 Hif1 alpha or Nrf2. Progressive hyperglycemia in Fh1bKO mice led to dysregulated metabolism in b 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 Fh1bKO mice was ameliorated after culture under normoglycemic conditions. These studies highlight the role of FH and dysregulated mitochondrial metabolism in T2D.

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