Fumarate Hydratase Deletion in Pancreatic β Cells Leads to Progressive Diabetes

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2017 Sep 28

PMID 28954230

Citations 34

Authors

Julie Adam

Reshma Ramracheya

Margarita V Chibalina

Nicola Ternette

Alexander Hamilton

Andrei I Tarasov

Quan Zhang

Eduardo Rebelato

Nils J G Rorsman

Rafael Martin-Del-Rio

Amy Lewis

Gizem Ozkan

Hyun Woong Do

Peter Spegel

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

Affiliations

Soon will be listed here.

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 [Ca] 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.

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