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This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/H2497    most recent 00873.2007v1 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 PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Saeedi, R. Articles by Allard, M. F. Search for Related Content PubMed PubMed Citation Articles by Saeedi, R. Articles by Allard, M. F.

Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms

¹Department of Pathology and Laboratory Medicine, James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia-Saint Paul's Hospital; and ²Department of Biochemistry and Molecular Biology, Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia; and ³Department of Pediatrics, Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada

Submitted 25 July 2007 ; accepted in final form 26 March 2008

The metabolic actions of the antidiabetic agent metformin reportedly occur via the activation of the AMP-activated protein kinase (AMPK) in the heart and other tissues in the presence or absence of changes in cellular energy status. In this study, we tested the hypothesis that metformin has AMPK-independent effects on metabolism in heart muscle. Fatty acid oxidation and glucose utilization (glycolysis and glucose uptake) were measured in isolated working hearts from halothane-anesthetized male Sprague-Dawley rats and in cultured heart-derived H9c2 cells in the absence or in the presence of metformin (2 mM). Fatty acid oxidation and glucose utilization were significantly altered by metformin in hearts and H9c2 cells. AMPK activity was not measurably altered by metformin in either model system, and no impairment of energetic state was observed in the intact hearts. Furthermore, the inhibition of AMPK by 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine (Compound C), a well-recognized pharmacological inhibitor of AMPK, or the overexpression of a dominant-negative form of AMPK failed to prevent the metabolic actions of metformin in H9c2 cells. The exposure of H9c2 cells to inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) or protein kinase C (PKC) partially or completely abrogated metformin-induced alterations in metabolism in these cells, respectively. Thus the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.

AMP-activated protein kinase; energy metabolism