The prevalence of type 2 diabetes mellitus is rising in the United States, with a recent estimate suggesting that 7% of the US population (or 21 million persons) have the disease.1 In addition to well-recognized contributions to coronary artery disease risk, the metabolic derangement of diabetes also can result in abnormalities of cardiac function (diabetic cardiomyopathy) that are likely independent of effects on the vasculature. Indeed, >3 decades ago, data from the Framingham Heart Study suggested that patients with type 2 diabetes mellitus have an increased risk of congestive heart failure that persists when adjusted for atherosclerotic disease.2 Although clinical appreciation of diabetic cardiomyopathy has since increased significantly, the mechanisms by which diabetes mellitus causes diastolic and systolic dysfunction in patients without epicardial coronary artery disease remain unclear. Article p 1170 Animal models of diabetic cardiomyopathy suggest that this phenotype may result in part from intrinsic abnormalities of cardiomyocyte energy use and lipid metabolism.3 The energy demands of the cardiac myocyte typically are met by ATP production from β-oxidation (oxidative phosphorylation) of fatty acids (FAs). FAs enter the cell via transport mechanisms (eg, FA transport protein-1 and CD-36), or through direct passive membrane diffusion. Fatty acids are then conjugated with acyl-CoA by the enzyme acyl-CoA synthase and transported to the mitochondria to undergo β-oxidation and thereby generate ATP for cellular energy needs. Fatty-acyl CoA not used for energy production can be esterified to tri-acyl glycerol (triglyceride) to provide an intracellular pool for FA storage. The deleterious effects of the accumulation of lipid and other toxic products of FA metabolism are called cardiac lipotoxicity and are presumed to be involved in the development of diabetic cardiomyopathy. Perhaps through increased signaling of the peroxisome proliferator–activated receptor-α system/PGC-1, which regulates mitochondrial substrate use, nonesterified acyl-CoA can accumulate and be detrimental …