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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/E155    most recent 90228.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Harney, J. A. Articles by Rodgers, R. L. PubMed PubMed Citation Articles by Harney, J. A. Articles by Rodgers, R. L.

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