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

Autor: Haythorne E; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. Elizabeth.Haythorne@dpag.ox.ac.uk., Lloyd M; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK., Walsby-Tickle J; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Tarasov AI; School of Biomedical Sciences, Ulster University, Coleraine, BT52 1SA, Northern Ireland, UK., Sandbrink J; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK., Portillo I; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK., Exposito RT; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.; Institute for Diabetes and Cancer (IDC), Helmholtz Center, Munich, Neuherberg, 85764, Germany., Sachse G; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.; Brandenburg Medical School (Theodor Fontane), ZTM-BB, Brandenburg a. d. H, 14770, Germany., Cyranka M; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK., Rohm M; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK.; Institute for Diabetes and Cancer (IDC), Helmholtz Center, Munich, Neuherberg, 85764, Germany., Rorsman P; Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, OX3 7LJ, UK., McCullagh J; Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK., Ashcroft FM; Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford, OX1 3PT, UK. frances.ashcroft@dpag.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Nov 14; Vol. 13 (1), pp. 6754. Date of Electronic Publication: 2022 Nov 14.
DOI: 10.1038/s41467-022-34095-x
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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