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        Diabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells

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        s41467_019_10189_x.pdf (PDF, 2Mb)
        Author
        Haythorne, Elizabeth
        Rohm, Maria
        van de Bunt, Martijn
        Brereton, Melissa F
        Tarasov, Andrei I
        Blacker, Thomas S
        Sachse, Gregor
        Silva Dos Santos, Mariana
        Terron Exposito, Raul
        Davis, Simon
        Baba, Otto
        Fischer, Roman
        Duchen, Michael R
        Rorsman, Patrik
        MacRae, James I
        Ashcroft, Frances M
        Attention
        2299/21609
        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.
        Publication date
        2019-06-06
        Published in
        Nature Communications
        Published version
        https://doi.org/10.1038/s41467-019-10189-x
        Other links
        http://hdl.handle.net/2299/21609
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