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.
Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Oxford, OX1 3PT, UK.
Mitochondria, Animals, Mice, Transgenic, Mice, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, NAD, Glucose, Potassium Channels, Inwardly Rectifying, Adenosine Triphosphate, Gene Expression Profiling, Proteomics, Oxidative Phosphorylation, Gluconeogenesis, Glycolysis, Oxygen Consumption, Insulin-Secreting Cells, Metabolomics, Insulin Secretion