title: Insulin-like stimulation of cardiac fuel metabolism by physiological levels of glucagon: involvement of PI3K but not cAMP.
abstract: 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 microM). 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 microM) 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.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Univ. of Rhode Island, 345 Fogarty Hall, Kingston, RI 02881, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Harney
authors.forename: Robert L
authors.initials: RL
authors.lastname: Rodgers
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002867:Chromones / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D002867:Chromones; D007328:Insulin; D009025:Morpholines; D010168:Palmitates; D047428:Protein Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D005934:Glucagon; D000242:Cyclic AMP; D019870:1-Phosphatidylinositol 4-Kinase; D051057:Proto-Oncogene Proteins c-akt; D000262:Adenylyl Cyclases; D005947:Glucose