AMP-Dependent Protein Kinase Activators

Abstract

See related articles, pages 403–411 A patent inability to properly use glycolytic and fatty acid substrates and progressive insulin resistance characterize non–insulin dependent diabetes mellitus. Curiously, the failing myocardium may also share these unfavorable characteristics. Insights from the clinical arena indicate a significant relationship between insulin resistance and New York Heart Association heart failure classification.1 In fact, insulin resistance may beget heart failure and heart failure may beget insulin resistance.2 Fueled by a recent resurgence in studies of the metabolic derangements contributing to cardiovascular disease, we are beginning to comprehend the complexities of metabolism or at least appreciate the bounds of our ignorance. Our understanding of such issues surrounding diabetes and heart failure is predicated on identifying the proximal regulators of substrate availability, sensing, and utilization. One potentially satisfying candidate appears to be AMP-dependent protein kinase (AMPK)3,4 and is the focus of the study by Gundewar et al in this issue of Circulation Research .5 AMPK has emerged as a principal figure in the story of metabolic regulation and dysregulation in diabetes, exercise, and, to a lesser extent, myocardial ischemia. AMPK activation appears to be beneficial in the context of myocardial ischemia and reperfusion, at least in terms of infarct size reduction. Such findings are confirmed by the present5 and previous studies.6 However, the intriguing element of the present study5 is the significant effect of chronic, postischemic treatment with the AMPK-activating biguanide metformin in the context of the failing heart (Figure). Despite a prior contraindication for heart failure because of concerns about the generation of lactic acidosis, interest has been renewed (although it actually never waned for some determined investigators) for the potential use of the insulin “sensitizer” metformin in diabetics with heart failure. Such interest is based not simply on the …