Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10189-x
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Funding
- Wellcome Trust [090532/Z/09/Z, G0900747 91070, 884655, 089795, 095531, FC001999]
- European Research Council (ERC) [322620]
- Novo Nordisk postdoctoral fellowships
- University of Oxford
- Royal Society/Wolfson Merit Award
- Francis Crick Institute
- UK Medical Research Council [FC001999]
- Kennedy Trust Fund
- Biotechnology and Biological Sciences Research Council [BB/P018726/1, BB/L020874/1]
- Cancer Research UK [FC001999]
- BBSRC [BB/L020874/1, BB/R017220/1] Funding Source: UKRI
- MRC [MR/T002107/1] Funding Source: UKRI
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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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