Glucose derived redox equivalents preserve PKA activity and glucagon secretion during hypoglycaemia
Frueh, A.; Katzilieris-Petras, G.; Pedersen, C. L.; Ekstrand, M. H.; Deshar, G.; Ialchina, R.; Paige, H. A.; Nielsen, D.; Andersen, D. B.; Holst, J. J.; Spegel, P.; Pedersen, P. A.; Knudsen, J. G.
Show abstract
The release of glucagon from pancreatic alpha cells is a core component of hypoglycaemic counter regulation. Several mechanisms regulate glucagon release including paracrine control by neighbouring cell types, and changes in extracellular glucose. While the inhibitory effect of glucose on glucagon secretion is well established, the exact way in which glucose metabolism contributes to alpha cell function remains unclear. Here, we use live-cell imaging of the redox potential in alpha cells within intact islets to investigate whether non-mitochondrial glucose metabolism contributes to the potentiation of glucagon secretion at low glucose. Our findings show that increased glucose metabolism through the pentose phosphate pathway elevates the cytosolic redox potential in alpha cells. Using a combination of antioxidant treatment and pre-incubation in 5 mM glucose, we find that the cytosolic redox potential affects PKA activity in alpha cells and that changes in whole body redox state affects the counterregulatory response in mice. These findings indicate that prior glucose-driven redox potential charging is essential for maintaining glucagon secretion at low glucose.
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