Skeletal muscle has a crucial role in substrate metabolism and energy balance and perturbations can have major implications for health, as exemplified by the important role of skeletal muscle insulin resistance in obesity and Type 2 diabetes mellitus (DM). A major focus of the candidate's research has been to better understand the interaction between glucose and fatty acid metabolism in the pathogenesis of skeletal muscle insulin resistance. This research has led to the hypothesis that skeletal muscle in obesity and Type 2 DM has a reduced capacity for fat oxidation, that this impairment is most clearly manifest during fasting conditions and causes lipid accumulation within muscle; a process that aggravates insulin resistant glucose metabolism. The thrust of this proposal is to further test this hypothesis. We will seek to do this by developing several novel approaches to the clinical investigation of skeletal muscle metabolism of fatty acids. During the past 11 years of clinical investigation, the candidate has mastered the use of arterio-venous leg balance, radioactive fatty acid and glucose isotope dilution, systemic and regional (limb) indirect calorimetry, euglycemic insulin infusions and percutaneous muscle biopsy as methods to evaluate skeletal muscle physiology in Type 2 DM and obesity. All of these techniques have been in use for at least several decades. This field of clinical investigation could benefit considerably by application of exciting new modalities, including non-invasive imaging of metabolism and tissue composition. During the next five years, with the support of a MidCareer Investigator Award, the candidate will work within a multidisciplinary collaborative effort, including young colleagues to develop three methods: 1) a stable isotope method for in vivo determination of fatty acid uptake and oxidation in skeletal muscle; 2) spiral magnetic resonance imaging method for non-invasive determination of skeletal muscle lipid content; and 3) positron emission tomography (PET) imaging of skeletal muscle fatty acid uptake and oxidation. These methods will be used for testing the hypothesis of that skeletal muscle oxidation of fatty acids is decreased while fatty acid esterification is increased in obesity-related insulin- resistance.
