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Lookup NU author(s): Dr Susan Aiston, Dr Laura Hampson, Dr Catherine ArdenORCiD, Professor Loranne Agius
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Aims/hypothesis: An insulin signalling pathway leading from activation of protein kinase B (PKB, also known as Akt) to phosphorylation (inactivation) of glycogen synthase kinase-3 (GSK-3) and activation of glycogen synthase is well characterised. However, in hepatocytes, inactivation of GSK-3 is not the main mechanism by which insulin stimulates glycogen synthesis. We therefore tested whether activation of PKB causes inactivation of glycogen phosphorylase. Materials and methods: We used a conditionally active form of PKB, produced using recombinant adenovirus, to test the role of acute PKB activation in the control of glycogen phosphorylase and glycogen synthesis in hepatocytes. Results: Conditional activation of PKB mimicked the inactivation of phosphorylase, the activation of glycogen synthase, and the stimulation of glycogen synthesis caused by insulin. In contrast, inhibition of GSK-3 caused activation of glycogen synthase but did not mimic the stimulation of glycogen synthesis by insulin. PKB activation and GSK-3 inhibition had additive effects on the activation of glycogen synthase, indicating convergent mechanisms downstream of PKB involving inactivation of either phosphorylase or GSK-3. Glycogen synthesis correlated inversely with the activity of phosphorylase-a, irrespective of whether this was modulated by insulin, by PKB activation or by a selective phosphorylase ligand, supporting an essential role for phosphorylase inactivation in the glycogenic action of insulin in hepatocytes. Conclusions/interpretation: In hepatocytes, the acute activation of PKB, but not the inhibition of GSK-3, mimics the stimulation of glycogen synthesis by insulin. This is explained by a pathway downstream of PKB leading to inactivation of phosphorylase, activation of glycogen synthase, and stimulation of glycogen synthesis, independent of the GSK-3 pathway. © Springer-Verlag 2005.
Author(s): Aiston S, Hampson LJ, Arden C, Iynedjian PB, Agius L
Publication type: Article
Publication status: Published
Journal: Diabetologia
Year: 2006
Volume: 49
Issue: 1
Pages: 174-182
ISSN (print): 0012-186X
ISSN (electronic): 1432-0428
Publisher: Springer Berlin
URL: http://dx.doi.org/10.1007/s00125-005-0068-4
DOI: 10.1007/s00125-005-0068-4
PubMed id: 16341839
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