Published online before print June 1, 2006, doi: 10.1161/01.RES.0000229656.05244.11
© 2006 American Heart Association, Inc.
Integrative Physiology |
Fatty Acids Attenuate Insulin Regulation of 5'-AMP–Activated Protein Kinase and Insulin Cardioprotection After Ischemia
From the Cardiovascular Research Group and Departments of Pediatrics (C.D.L.F., G.D.L.) and Pharmacology (C.D.L.F., A.S.C.), University of Alberta, Edmonton, Canada.
Correspondence to Dr Gary D. Lopaschuk, 423 Heritage Medical Research Building, The University of Alberta, Edmonton, Alberta T6G 2S2, Canada. E-mail gary.lopaschuk{at}ualberta.ca
The cardioprotective effect of insulin during ischemia–reperfusion has been associated with stimulation of glucose uptake and glycolysis. Although fatty acids and 5'-AMP activated protein kinase (AMPK) are regulators of glucose metabolism, it is unknown what effect insulin has on postischemic function and AMPK activity in the presence of high levels of fatty acid. Isolated ejecting mouse hearts were perfused with Krebs–Henseleit solution containing 5 mmol · L–1 glucose and 0, 0.2, or 1.2 mmol · L–1 palmitate, with or without 100 µU/mL insulin. During aerobic perfusion in the absence of palmitate, insulin stimulated glycolysis by 73% and glucose oxidation by 54%, while inhibiting AMPK activity by 43%. In the presence of 0.2 or 1.2 mmol · L–1 palmitate, insulin stimulated glycolysis by 111% and 105% and glucose oxidation by 72% and 274% but no longer inhibited AMPK activity. During reperfusion of hearts in the absence of palmitate, insulin increased recovery of cardiac power by 47%. This was associated with a 97% increase in glycolysis and a 160% increase in glucose oxidation. However, in the presence of 1.2 mmol · L–1 palmitate, insulin now decreased recovery of cardiac power by 42%. During reperfusion, glucose oxidation was inhibited by high fat, but insulin-stimulated glycolysis remained high, resulting in increased proton production. In the absence of fatty acids, insulin blunted the ischemia-induced activation of AMPK, but this effect was lost in the presence of fatty acids. We demonstrate that the cardioprotective effect of insulin and its ability to inhibit AMPK activity are lost in the presence of high concentrations of fatty acids.
Key Words: fatty acid oxidation • glucose oxidation • glycolysis • proton production • ischemia–reperfusion
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