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Haythorne, E.* ; Lloyd, M.* ; Walsby-Tickle, J.* ; Tarasov, A.I.* ; Sandbrink, J.* ; Portillo, I.* ; Terron Exposito, R. ; Sachse, G.* ; Cyranka, M.* ; Rohm, M. ; Rorsman, P.* ; McCullagh, J.* ; Ashcroft, F.M.*

Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells.

Nat. Commun. 13:6754 (2022)

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Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved. Using isolated islets and INS-1 cells, we show here that one or more glycolytic metabolites downstream of phosphofructokinase and upstream of GAPDH mediates the effects of chronic hyperglycemia. This metabolite stimulates marked upregulation of mTORC1 and concomitant downregulation of AMPK. Increased mTORC1 activity causes inhibition of pyruvate dehydrogenase which reduces pyruvate entry into the tricarboxylic acid cycle and partially accounts for the hyperglycaemia-induced reduction in oxidative phosphorylation and insulin secretion. In addition, hyperglycaemia (or diabetes) dramatically inhibits GAPDH activity, thereby impairing glucose metabolism. Our data also reveal that restricting glucose metabolism during hyperglycaemia prevents these changes and thus may be of therapeutic benefit. In summary, we have identified a pathway by which chronic hyperglycaemia reduces β-cell function.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

ISSN (print) / ISBN 2041-1723

e-ISSN 2041-1723

Journal Nature Communications

Quellenangaben Volume: 13, Issue: 1, Article Number: 6754

Publisher Nature Publishing Group

Publishing Place London

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Cancer (IDC)

Grants RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)
RCUK | MRC | Medical Research Foundation