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

Elizabeth Haythorne, Maria Rohm, Martijn van de 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, Frances M. Ashcroft

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17 Citations (Scopus)

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.

Original languageEnglish
Article number2474
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - 1 Dec 2019

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    Haythorne, E., Rohm, M., van de Bunt, M., Brereton, M. F., Tarasov, A. I., Blacker, T. S., Sachse, G., Silva dos Santos, M., Terron Exposito, R., Davis, S., Baba, O., Fischer, R., Duchen, M. R., Rorsman, P., MacRae, J. I., & Ashcroft, F. M. (2019). Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells. Nature Communications, 10(1), [2474]. https://doi.org/10.1038/s41467-019-10189-x