10779/crick.11550702.v1 Elizabeth Haythorne Elizabeth Haythorne Maria Rohm Maria Rohm Martijn van de Bunt Martijn van de Bunt Melissa F Brereton Melissa F Brereton Andrei I Tarasov Andrei I Tarasov Thomas S Blacker Thomas S Blacker Gregor Sachse Gregor Sachse Mariana Silva Dos Santos Mariana Silva Dos Santos Raul Terron Exposito Raul Terron Exposito Simon Davis Simon Davis Otto Baba Otto Baba Roman Fischer Roman Fischer Michael R Duchen Michael R Duchen Patrik Rorsman Patrik Rorsman James I MacRae James I MacRae Frances M Ashcroft Frances M Ashcroft Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells. The Francis Crick Institute 2020 Adenosine Triphosphate Animals Diabetes Mellitus, Experimental Diabetes Mellitus, Type 2 Gene Expression Profiling Gluconeogenesis Glucose Glycolysis Insulin Secretion Insulin-Secreting Cells Metabolomics Mice Mice, Transgenic Mitochondria NAD Oxidative Phosphorylation Oxygen Consumption Potassium Channels, Inwardly Rectifying Proteomics MET 2020-01-08 17:01:11 Journal contribution https://crick.figshare.com/articles/journal_contribution/Diabetes_causes_marked_inhibition_of_mitochondrial_metabolism_in_pancreatic_-cells_/11550702 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.