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Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic beta-cells

Journal article
Authors E. Haythorne
M. Rohm
M. van de Bunt
M. F. Brereton
A. I. Tarasov
T. S. Blacker
G. SachseqF
M. S. dos Santos
R. T. Exposito
S. Davis
O. Baba
R. Fischer
M. R. Duchen
Patrik Rorsman
J. I. MacRae
Frances M. Ashcroft
Published in Nature Communications
Volume 10
ISSN 2041-1723
Publication year 2019
Published at Institute of Neuroscience and Physiology
Language en
Links dx.doi.org/10.1038/s41467-019-10189...
Keywords insulin-secretion, gene-expression, glucose, islets, state, transcriptome, dysfunction, mechanisms, nadh, mass
Subject categories Diabetology

Abstract

Diabetes is a global health problem caused primarily by the inability of pancreatic beta-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of beta-cells to respond to glucose in type-2 diabetes remain unresolved. Using a combination of transcriptomics and proteomics, we find significant dysregulation of major metabolic pathways in islets of diabetic beta V59M mice, a non-obese, eulipidaemic diabetes model. Multiple genes/proteins involved in glycolysis/gluconeogenesis are upregulated, whereas those involved in oxidative phosphorylation are downregulated. In isolated islets, glucose-induced increases in NADH and ATP are impaired and both oxidative and glycolytic glucose metabolism are reduced. INS-1 beta-cells cultured chronically at high glucose show similar changes in protein expression and reduced glucose-stimulated oxygen consumption: targeted metabolomics reveals impaired metabolism. These data indicate hyperglycaemia induces metabolic changes in beta-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of beta-cells in diabetes.

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