Cardiac substrate metabolism in type 2 diabetes.

As the most metabolically demanding organ on a per gram basis, substrate metabolism in the heart is intricately linked to cardiac function. Virtually all major cardiovascular pathologies are associated with perturbations in cardiac substrate metabolism, and increasing evidence supports that these perturbations in substrate metabolism can directly contribute to cardiac dysfunction. Furthermore, type 2 diabetes (T2D) is a major risk factor for increased cardiovascular disease burden, while also being characterized by a very distinct metabolic profile in the heart. This includes increases in cardiac fatty oxidation rates and a robust reduction in cardiac glucose oxidation rates. Herein, we will describe the primary mechanisms responsible for the increase in cardiac fatty acid oxidation and decrease in cardiac glucose oxidation during T2D, while also detailing perturbations in cardiac ketone and amino acid metabolism. In addition, we will interrogate preclinical studies that have addressed whether correcting perturbations in cardiac substrate metabolism may have clinical utility against ischemic heart disease, diabetic cardiomyopathy, or heart failure associated with T2D. Lastly, we will consider the translational potential of such an approach to manage cardiovascular disease in people living with T2D.