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.