Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34095-x
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Funding
- UK Medical Research Council [MR/T002107/1]
- Biotechnology and Biological Sciences Research Council [BB/R017220/1, BB/R013829/1]
- John Fell Fund [006657]
- Nuffield Benefaction for Medicine/Wellcome Institutional Strategic Support Fund (Oxford MSIF grant) [0007293]
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Chronic hyperglycemia impairs insulin secretion and leads to diabetes. It has been found that a glucose metabolite is responsible for this effect, and reducing glucose metabolism during hyperglycemia can prevent the loss of beta-cell function.
Chronic hyperglycemia impairs insulin secretion from pancreatic beta cells in diabetes. Here, the authors reveal that a glucose metabolite is responsible and show lowering glucose metabolism during hyperglycemia prevents loss of beta-cell function. Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic beta-cells. This underlies the progressive decline in beta-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 beta-cell function.
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