University of Hertfordshire

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  • 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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Original languageEnglish
Article number2474
Number of pages17
JournalNature Communications
Journal publication date6 Jun 2019
Volume10
Issue1
DOIs
Publication statusPublished - 6 Jun 2019

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.

ID: 16946332