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The effect of glucose on cardiac AMP-activated protein kinase

Tabidi, I.; (2009) The effect of glucose on cardiac AMP-activated protein kinase. Doctoral thesis , UCL (University College London). Green open access

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AMP-activated protein kinase (AMPK) serves as an energy-sensing protein that is activated by a variety of metabolic stresses. Recent studies suggest that AMPK is also regulated by hormones and by nutrients such as glucose and fatty acids. In skeletal muscle it was previously shown that AMPK activity was decreased with increasing glucose concentration. In the present study both the activity and the Threonine-172 phosphorylation of AMPK in incubated rat ventricular cardiac myocytes were found to be decreased by increasing glucose in the presence and absence of palmitate. Glucose also caused a decrease in the AMPK-driven phosphorylation of acetyl-CoA carboxylase. Measurements of the myocyte contents of ATP, ADP, AMP and glycogen showed that the effect of glucose on AMPK activity could not be secondary to changes in the levels of these metabolites. The decrease in AMPK activity with glucose was additive to and distinct from the effect of insulin which is mediated through protein kinase B (PKB). Increasing glucose concentration had no effect on the phosphorylation of Threonine-308 and Serine-473 in PKB. AICAR, a pharmacological activator of AMPK, had no effect on the ability of glucose to inactivate AMPK. The myocyte content of the pentose phosphate pathway (PPP) metabolite xylulose 5-phosphate (Xu5P), a known allosteric activator of PP2A, was increased with increasing glucose concentration such that AMPK activity was inversely related to Xu5P content. The glucose 6-phosphate dehydrogenase inhibitor diehydroepiandeosterone (DHA) and thiamine, the precursor of the coenzyme for transketolase, both increased AMPK activity whereas the NADPH oxidant phenazine methosulphate (PMS) decreased AMPK activity. DHA and PMS respectively decreased and increased flux through the PPP. The findings suggest that inactivation of AMPK by glucose may be mediated by the activity of the PPP which sets the level of Xu5P. Two other findings were also made during the course of this project. First, the activity of phosphofructokinase-2 (PFK-2) in the perfused heart was previously shown to be activated through phosphorylation by AMPK. It was therefore expected that increasing glucose concentration would decrease myocyte PFK-2 activity. However PFK-2 activity was found to be increased by glucose. Second, the phosphorylation of Threonine-308 in PKB in response to insulin was appreciably increased in the presence of AICAR suggesting that there may be crosstalk between AMPK and the insulin signalling pathway at the level of PKB.

Type: Thesis (Doctoral)
Title: The effect of glucose on cardiac AMP-activated protein kinase
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/18944
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