Metabolic modulation of pyruvate dehydrogenase and glucose oxidation in diabetic cardiomyopathy: pathways,...

Individuals living with obesity and/or type 2 diabetes (T2D) are at a disproportionately high risk of developing cardiovascular disease. This includes diabetic cardiomyopathy (DbCM), a condition characterized by left ventricular diastolic dysfunction that is often present in individuals with pre- or early-stage T2D. Although there are numerous mediators that contribute to the development of DbCM, perturbations in cardiac substrate metabolism are widely believed to play a major role in its pathogenesis. In particular, myocardial glucose oxidation is often suppressed due to decreased activity of the pyruvate dehydrogenase (PDH) complex, the rate-limiting enzyme of glucose oxidation, which is responsible for decarboxylating pyruvate to acetyl CoA, thus acting as the link between glycolysis and oxidative phosphorylation of glucose. Importantly, numerous preclinical studies suggest that restoring suppressed myocardial glucose oxidation can alleviate DbCM. In this review, we will describe the major perturbations that characterize myocardial substrate metabolism in T2D, while discussing the primary pharmacological approaches that have been pursued to stimulate myocardial PDH activity and glucose oxidation. We will also highlight potential mechanisms explaining how increasing myocardial PDH activity and glucose oxidation favorably influence diastolic function. Given the increasing prevalence of DbCM in the human population, it is not only imperative to better understand its pathophysiology but also to develop novel therapies for its management, which may also have utility in the management of heart failure with preserved ejection fraction.