Interaction of insulin and AMPK in the ischemic heart: another chapter in the book of metabolic therapy?

There has been a longstanding interest in the development of metabolic modulations to improve the outcome of myocardial ischemia. The glucose-insulinpotassium (GIK) regimen presents the classic example of such a quest. For more than four decades since GIK was first described, substantial evidence from animal research and small size clinical studies has supported the efficacy of GIK treatment for acute myocardial ischemia.1–3 However, a recent large clinical trial, CREATE-ECLA, showed no effect of GIK in patients with acute ST-segment elevation myocardial infarction.1,4 Although this is extremely disappointing for supporters of metabolic treatment, careful evaluations of why GIK got lost in translation will benefit future development of therapeutic strategies based on metabolic principles. The study by Folmes et al published in this issue of Circulation Research sheds some light on this matter.5 Decreased perfusion during myocardial ischemia limits the delivery of oxygen and nutrients and decreases oxidative metabolism. Under these conditions, increased glycolytic ATP production becomes a critical energy source (Figure). Several mechanisms have been proposed to account for the increases in glucose uptake and glycolysis during myocardial ischemia. These include: -adrenergic mechanisms, p38 activation, and, more recently, stimulation of AMPK-activated protein kinase (AMPK).6–9 AMPK acts as an intracellular energy sensor. Its activity is highly sensitive to the cellular AMP to ATP ratio. AMPK activity markedly increases in response to energy depletion (increased AMP/ATP) during myocardial ischemia.8,10 Previous studies suggested that the increased AMPK activity promoted glycolytic ATP production and, thereby, protected against ischemic injury.8,11 It was also suggested, however, that stimulation of fatty acid oxidation by AMPK during reperfusion was detrimental to postischemic recovery. This is because increased fatty acid oxidation would suppress glucose oxidation, whereas continued glycolysis will result in cytosolic proton production and intracellular acidosis5,10 (Figure). This uncoupling between the rates of glycolysis and glucose oxidation could be exaggerated when enhanced glycolysis occurred in the presence of high circulating fatty acids, because the latter would facilitate fatty acid oxidation, which suppresses glucose oxidation, thereby increasing the “uncoupling” and predisposing the reperfused myocardium to further injury. Multiple mechanisms have been proposed to explain the benefit of providing insulin and glucose to ischemic hearts (Figure). First, this regimen enhances glycolytic ATP production during restricted perfusion and impaired oxidative ATP production. Second, high insulin will suppress the high blood fatty acid levels that are commonly observed in patients with acute ischemic syndrome. Third, activation of PI3K/Akt signaling by insulin promotes cell survival and protects against apoptosis. Finally, recent studies suggest that insulin, via activation of Akt, inhibits AMPK activity by phosphorylation of Ser 485 of -AMPK.12,13 This interesting finding provides a mechanism by which insulin could antagonize the adverse effects of AMPK in postischemic hearts. The study by Folmes et al critically tested this hypothesis in isolated mouse hearts. They reported that although insulin inhibited AMPK activity and improved postischemic recovery in hearts perfused with glucose as the only substrate, the inhibitory effect of insulin on AMPK activity was not observed when palmitate was present in the perfusate at either low (0.2 mmol/L) or high (1.2 mmol/L) concentration. Furthermore, in contrast to the improved function observed in glucose-perfused hearts treated with insulin, insulin impaired the post-ischemic recovery in hearts perfused with the high concentration of palmitate. Although this study was performed in vitro it illustrates several important considerations regarding metabolic modulation for the management of myocardial ischemia. One critical issue is the level of circulating fatty acids to which the heart is exposed during ischemia and reperfusion. The study reports that high levels of fatty acids, commonly observed in patients during acute stress, abolished the benefit of insulin. This result suggests that the insulin effects observed in ex vivo animal studies may not extend to clinical situations. However, a potential effect of GIK treatment is the insulinmediated suppression of circulating fatty acid levels. If so, the peripheral effect of insulin may also serve or contribute to its cardiac action. Such an effect was only tested in small groups of patients in early studies of GIK treatment when the management of myocardial ischemia was drastically different from that of today. Low-molecular weight heparin used during reperfusion therapy releases lipoprotein lipase into circulation that could counteract the lowering of free fatty acids by insulin, thus the effect of insulin on plasma levels of free fatty acids should be reevaluated in today’s clinical studies. The study by Folmes et al also suggests that the amount of insulin supplied to the heart might contribute to the differenThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass. Correspondence to Rong Tian, MD, PhD, 221 Longwood Avenue, Room 252, Boston, MA 02115. E-mail [email protected] (Circ Res. 2006;99:3-5.) © 2006 American Heart Association, Inc.