Substrate metabolism in the diabetic heart: Relationship to the observed cardiac dysfunction and the significance of putative mechanisms in the control of lipid utilization

Diabetic individuals are at increased risk for the development of cardiovascular disease. Not all of the increased risk can be accounted for by atherosclerosis and coronary artery disease. The existence of a diabetic cardiomyopathy has been postulated. Hearts from diabetic db/db mice (a type 2 diabetic model) display an increased reliance on fatty acids for cardiac energy generation and it has been suggested that this is related to the impaired myocardial function of both in vivo and ex vivo perfused db/db hearts. Therefore it was undertaken to determine if chronic manipulation of substrate supply to the heart through the use of an insulin sensitizer could lead to alterations in cardiac metabolism of isolated db/db hearts. Corrections in the diabetic status of db/db mice led to normalization of their cardiac metabolism; however this was without effect on cardiac function measured either in vivo through echocardiography, or via ex vivo perfusion. These observations were similarly confirmed with the use of another pharmacological agent. The increased reliance on FA by isolated db/db hearts was not evident in mitochondria isolated from db/db mouse hearts. Uncoupling protein 3, which has been postulated to be involved in FA metabolism, was not found to be elevated in hearts from db/db mice.