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

Elizabeth Haythorne, Maria Rohm, Martijn Bunt, Melissa F. Brereton, Andrei I. Tarasov, Thomas S. Blacker, Gregor Sachse, Mariana Silva dos Santos, Raul Terron Exposito, Simon Davis, Otto Baba, Roman Fischer, Michael R. Duchen, Patrik Rorsman, James I. MacRae and Frances M. Ashcroft ()
Additional contact information
Elizabeth Haythorne: University of Oxford
Maria Rohm: University of Oxford
Martijn Bunt: University of Oxford, Churchill Hospital
Melissa F. Brereton: University of Oxford
Andrei I. Tarasov: University of Oxford, Churchill Hospital
Thomas S. Blacker: University College London
Gregor Sachse: University of Oxford
Mariana Silva dos Santos: The Francis Crick Institute
Raul Terron Exposito: University of Oxford
Simon Davis: University of Oxford
Otto Baba: Tokushima University Graduate School
Roman Fischer: University of Oxford
Michael R. Duchen: University College London
Patrik Rorsman: University of Oxford, Churchill Hospital
James I. MacRae: The Francis Crick Institute
Frances M. Ashcroft: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Diabetes is a global health problem caused primarily by the inability of pancreatic β-cells to secrete adequate levels of insulin. The molecular mechanisms underlying the progressive failure of β-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 βV59M 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 β-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 β-cells that markedly reduce mitochondrial metabolism and ATP synthesis. We propose this underlies the progressive failure of β-cells in diabetes.

Date: 2019
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DOI: 10.1038/s41467-019-10189-x

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