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Insulin-like stimulation of cardiac fuel metabolism by physiological levels of glucagon: involvement of PI3K but not cAMP

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island

Submitted 11 February 2008 ; accepted in final form 14 May 2008

At concentrations around 10^–9 M or higher, glucagon increases cardiac contractility by activating adenylate cyclase/cyclic adenosine monophosphate (AC/cAMP). However, blood levels in vivo, in rats or humans, rarely exceed 10^–10 M. We investigated whether physiological concentrations of glucagon, not sufficient to increase contractility or ventricular cAMP levels, can influence fuel metabolism in perfused working rat hearts. Two distinct glucagon dose-response curves emerged. One was an expected increase in left ventricular pressure (LVP) occurring between 10^–9.5 and 10^–8 M. The elevations in both LVP and ventricular cAMP levels produced by the maximal concentration (10^–8 M) were blocked by the AC inhibitor NKY80 (20 µM). The other curve, generated at much lower glucagon concentrations and overlapping normal blood levels (10^–11 to 10^–10 M), consisted of a dose-dependent and marked stimulation of glycolysis with no change in LVP. In addition to stimulating glycolysis, glucagon (10^–10 M) also increased glucose oxidation and suppressed palmitate oxidation, mimicking known effects of insulin, without altering ventricular cAMP levels. Elevations in glycolytic flux produced by either glucagon (10^–10 M) or insulin (4 x 10^–10 M) were abolished by the phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 (10 µM) but not significantly affected by NKY80. Glucagon also, like insulin, enhanced the phosphorylation of Akt/PKB, a downstream target of PI3K, and these effects were also abolished by LY-294002. The results are consistent with the hypothesis that physiological levels of glucagon produce insulin-like increases in cardiac glucose utilization in vivo through activation of PI3K and not AC/cAMP.

insulin; glycolysis; phosphoinositide 3-kinase; cyclic adenosine monophosphate

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