Diabetes mellitus is a disease characterized by abnormal substrate flow and concentration. This chapter deals with metabolism of the heart. For the purposes of clarity, this treatise has been divided into subsections of carbohydrate, lipid, and protein metabolism of the heart during diabetes mellitus. Since diabetes mellitus is a disease which is typified by abnormal carbohydrate metabolism, it is essential to discuss how the factors regulate carbohydrate metabolism and the implications of the relationships to diabetes. Lipid metabolism in the heart is stimulated during diabetes mellitus. In insulin-dependent diabetic patients, basal energy expenditure, as monitored by indirect calorimetry, was found to be highly elevated in comparison to normal, control values. Glycogen degradation may be altered in the heart during diabetes. Weight loss is characteristic of insulin-dependent diabetes. This is not only a result of depletion of body fat deposits but also due to an accelerated rate of muscular protein degradation.