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 language | English |
|---|---|
| Article number | 2474 |
| Journal | Nature Communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published (in print/issue) - 1 Dec 2019 |
Funding
We thank Steve Ashcroft for advice on how to measure glycolysis, James McCullagh for helpful discussion, Idoia Portillo for technical assistance and the animal house staff for animal care. We thank Ana Teixeira and the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant 090532/ Z/09/Z and MRC Hub grant G0900747 91070) for generation of the RNA Sequencing data. We thank the Wellcome Trust (grants 884655, 089795 to F.M.A. and 095531 to P. R.) and the European Research Council (ERC Advanced grant 322620) for support. M.R. and M.v.d.B. were supported by Novo Nordisk postdoctoral fellowships run in partnership with the University of Oxford. F.M.A. held a Royal Society/Wolfson Merit Award and an ERC Advanced Investigatorship. Metabolomics was supported by the Francis Crick Institute, core funded by Cancer Research UK (FC001999), the UK Medical Research Council (FC001999) and the Wellcome Trust (FC001999). R.F. was supported by the Kennedy Trust Fund and mass spectrometric analysis was performed in the TDI MS Laboratory led by Benedikt M. Kessler. T.S.B. and M.R.D. were supported by the Biotechnology and Biological Sciences Research Council (BB/P018726/1 and BB/ L020874/1).
