Abstract
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.
Original language | English |
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Article number | 6754 |
Number of pages | 19 |
Journal | Nature Communications |
Volume | 13 |
Issue number | 1 |
Early online date | 14 Nov 2022 |
DOIs | |
Publication status | Published online - 14 Nov 2022 |
Bibliographical note
Funding Information:We thank Dr. Steve Ashcroft for valuable discussions and Dr. Thomas Hill for technical help. We thank the animal house staff for animal care. We thank the UK Medical Research Council (MR/T002107/1 to F.M.A., P.R. and E.H.), the Biotechnology and Biological Sciences Research Council (BB/R017220/1 to F.M.A. and BB/R013829/1 to J.M.), the John Fell Fund (006657 to E.H.) and the Nuffield Benefaction for Medicine/Wellcome Institutional Strategic Support Fund (Oxford MSIF grant 0007293 to E.H.) for support.
Publisher Copyright:
© 2022, The Author(s).
Keywords
- Diabetes Mellitus - metabolism
- Glucose - metabolism
- Glycolysis - physiology
- Humans
- Hyperglycemia - metabolism
- Insulin - metabolism
- Islets of Langerhans - metabolism
- Mechanistic Target of Rapamycin Complex 1 - metabolism
- Pyruvic Acid - metabolism