Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells.
journal contributionposted on 08.01.2020, 17:01 by 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
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.
Crick (Grant ID: 10012, Grant title: Macrae FC001999)
Adenosine TriphosphateAnimalsDiabetes Mellitus, ExperimentalDiabetes Mellitus, Type 2Gene Expression ProfilingGluconeogenesisGlucoseGlycolysisInsulin SecretionInsulin-Secreting CellsMetabolomicsMiceMice, TransgenicMitochondriaNADOxidative PhosphorylationOxygen ConsumptionPotassium Channels, Inwardly RectifyingProteomicsMET