The insulin resistant states of obesity and type 2 diabetes mellitus are associated with increased rates of cardiovascular disease, including myocardial dysfunction even in the absence of manifest vascular disease. These conditions are associated with abnormalities in skeletal muscle metabolism, and specifically with an impaired capacity to move between fuel substrates. PET and SPECT measurements of myocardial glucose or fat oxidation in obese and diabetic subjects have produced conflicting and ultimately inconclusive results. In order to proceed with studies of physiologic and pharmacologic modulators of myocardial fuel selection states of insulin resistance, new tools must be developed which allow definitive demonstration and quantification of differences in fuel selection associated with insulin resistance. We have developed a novel PET labeled free fatty acid, 16-[18F]-thiapalmitic acid (FTP), which provides quantitative index of rates of fatty acid oxidation. We propose to apply this tracer in combination with 1-[11C]- acetate, which allows simultaneous quantitation of tissue perfusion and total oxidative metabolism. We hypothesize that combined quantification of myocardial fatty acid oxidation, total oxidation, and blood flow using an acetate/FTP PET protocol provides sufficient information to distinguish abnormalities in myocardial metabolism associated with obesity and insulin resistance under fasting and insulin-stimulated conditions. The main objective of this proposal is to determine the ability of this novel PET approach to demonstrate differences in myocardial metabolism between lean and obese/insulin resistant humans. Paired studies in lean and obese subjects will be undertaken under fasting (fatty acid dominant, Aim 1) and hyperinsulinemic euglycemic clamp (carbohydrate dominant, Aim 2) conditions. Assuming that this PET approach proves able to demonstrate differences between lean and obese subjects, we pain to subsequently apply it in studies exploring the determinants of myocardial metabolism in patients with insulin resistance or diabetes. [unreadable] [unreadable]