Abstract-Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. This review discusses the latest findings in diabetic humans and in animal models and reviews emerging new mechanisms that may be involved in the development and progression of cardiac dysfunction in diabetes. (Circulation. 2007;115:3213-3223.)Key Words: diabetes mellitus Ⅲ fatty acids Ⅲ heart failure Ⅲ metabolism Ⅲ obesity T he prevalence of diabetes mellitus is growing rapidly. It is estimated that globally the number of adults affected with diabetes will increase from 135 million in 1995 to 300 million by 2025. 1 Patients with diabetes mellitus are at increased risk for cardiovascular diseases. Thus, cardiovascular complications are the leading cause of diabetes-related morbidity and mortality. 2 Diabetes mellitus is responsible for diverse cardiovascular complications such as increased atherosclerosis in large arteries (carotids, aorta, and femoral arteries) and increased coronary atherosclerosis, which increases the risk for myocardial infarction, stroke, and limb loss. Microangiopathy contributes to retinopathy and renal failure and may contribute to cardiac pathology as well. 3,4 Diabetes mellitus also can affect cardiac structure and function in the absence of changes in blood pressure and coronary artery disease, a condition called diabetic cardiomyopathy. This term was introduced 30 years ago by Rubler et al, 5 who described 4 diabetic patients with congestive heart failure and normal coronary arteries. Since then, diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs independently of coronary artery disease and hypertension. In addition, diabetic cardiomyopathy may be characterized by diastolic dysfunction, which becomes more apparent in the presence of hypertension or myocardial ischemia (discussed in detail in the next section). Human StudiesMany epidemiological and clinical studies have suggested the existence of a diabetic cardiomyopathy in humans. 2,6 -9 Diabetes mellitus is a well-recognized risk factor for developing heart failure. Indeed, the Framingham Heart Study showed that the frequency of heart failure is twice in diabetic men and five times in diabetic women compared with age-matched control subjects. 10 This increased incidence of heart failure in diabetic patients persisted despite correction for age, hypertension, obesity, hypercholesterolemia, and coronary artery disease. Studies using independent population databases have provided similar results, revealing increased heart failure rates in subjects with diabetes mellitus in cross-sectional analyses and increased risk for developing heart failure in prospective analyses, even after correction for confounding variables. [11][12][13] Echocardiographic c...

Pyruvate constitutes a critical branch point in cellular carbon metabolism. We have identified two proteins, Mpc1 and Mpc2, as essential for mitochondrial pyruvate transport in yeast, Drosophila, and humans. Mpc1 and Mpc2 associate to form an ~150-kilodalton complex in the inner mitochondrial membrane. Yeast and Drosophila mutants lacking MPC1 display impaired pyruvate metabolism, with an accumulation of upstream metabolites and a depletion of tricarboxylic acid cycle intermediates. Loss of yeast Mpc1 results in defective mitochondrial pyruvate uptake, and silencing of MPC1 or MPC2 in mammalian cells impairs pyruvate oxidation. A point mutation in MPC1 provides resistance to a known inhibitor of the mitochondrial pyruvate carrier. Human genetic studies of three families with children suffering from lactic acidosis and hyperpyruvatemia revealed a causal locus that mapped to MPC1, changing single amino acids that are conserved throughout eukaryotes. These data demonstrate that Mpc1 and Mpc2 form an essential part of the mitochondrial pyruvate carrier.

The gene encoding the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) was targeted in mice. PGC-1α null (PGC-1α−/−) mice were viable. However, extensive phenotyping revealed multi-system abnormalities indicative of an abnormal energy metabolic phenotype. The postnatal growth of heart and slow-twitch skeletal muscle, organs with high mitochondrial energy demands, is blunted in PGC-1α−/− mice. With age, the PGC-1α−/− mice develop abnormally increased body fat, a phenotype that is more severe in females. Mitochondrial number and respiratory capacity is diminished in slow-twitch skeletal muscle of PGC-1α−/− mice, leading to reduced muscle performance and exercise capacity. PGC-1α−/− mice exhibit a modest diminution in cardiac function related largely to abnormal control of heart rate. The PGC-1α−/− mice were unable to maintain core body temperature following exposure to cold, consistent with an altered thermogenic response. Following short-term starvation, PGC-1α−/− mice develop hepatic steatosis due to a combination of reduced mitochondrial respiratory capacity and an increased expression of lipogenic genes. Surprisingly, PGC-1α−/− mice were less susceptible to diet-induced insulin resistance than wild-type controls. Lastly, vacuolar lesions were detected in the central nervous system of PGC-1α−/− mice. These results demonstrate that PGC-1α is necessary for appropriate adaptation to the metabolic and physiologic stressors of postnatal life.

OBJECTIVE-In obesity and diabetes, myocardial fatty acid utilization and myocardial oxygen consumption (MVO 2 ) are increased, and cardiac efficiency is reduced. Mitochondrial uncoupling has been proposed to contribute to these metabolic abnormalities but has not been directly demonstrated. RESEARCH DESIGN AND METHODS-Oxygen consumptionand cardiac function were determined in db/db hearts perfused with glucose or glucose and palmitate. Mitochondrial function was determined in saponin-permeabilized fibers and proton leak kinetics and H 2 O 2 generation determined in isolated mitochondria.RESULTS-db/db hearts exhibited reduced cardiac function and increased MVO 2 . Mitochondrial reactive oxygen species (ROS) generation and lipid and protein peroxidation products were increased. Mitochondrial proliferation was increased in db/db hearts, oxidative phosphorylation capacity was impaired, but H 2 O 2 production was increased. Mitochondria from db/db mice exhibited fatty acid-induced mitochondrial uncoupling that is inhibitable by GDP, suggesting that these changes are mediated by uncoupling proteins (UCPs). Mitochondrial uncoupling was not associated with an increase in UCP content, but fatty acid oxidation genes and expression of electron transfer flavoproteins were increased, whereas the content of the F1 ␣-subunit of ATP synthase was reduced.CONCLUSIONS-These data demonstrate that mitochondrial uncoupling in the heart in obesity and diabetes is mediated by activation of UCPs independently of changes in expression levels. This likely occurs on the basis of increased delivery of reducing equivalents from ␤-oxidation to the electron transport chain, which coupled with decreased oxidative phosphorylation capacity increases ROS production and lipid peroxidation.

Diabetes is associated with increased incidence of heart failure even after controlling for coronary artery disease and hypertension. Thus, as diabetic cardiomyopathy has become an increasingly recognized entity among clinicians, a better understanding of its pathophysiology is necessary for early diagnosis and the development of treatment strategies for diabetes-associated cardiovascular dysfunction. We will review recent basic and clinical research into the manifestations and the pathophysiological mechanisms of diabetic cardiomyopathy. The discussion will be focused on the structural, functional and metabolic changes that occur in the myocardium in diabetes and how these changes may contribute to the development of diabetic cardiomyopathy in affected humans and relevant animal models.