Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms.
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.
Saeedi
Ramesh
R
Department of Pathology and Laboratory Medicine, James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, University of British Columbia-Saint Paul's Hospital, Canada.
Parsons
Hannah L
HL
Wambolt
Richard B
RB
Paulson
Kim
K
Sharma
Vijay
V
Dyck
Jason R B
JR
Brownsey
Roger W
RW
Allard
Michael F
MF
D055372:AMP-Activated Protein Kinases; D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002460:Cell Line; D004734:Energy Metabolism / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D010725:Phosphocreatine / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014280:Triglycerides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000227:Adenine Nucleotides; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D047428:Protein Kinase Inhibitors; D014280:Triglycerides; D010725:Phosphocreatine; D006003:Glycogen; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose