Insulin resistant glucose metabolism is commonly present and usually severe in type 2 diabetes mellitus (DM), and can often be modified by lifestyle interventions such as weight loss and/or exercise. Recent evidence from the Diabetes Prevention Program shows that lifestyle interventions in people at risk for type 2 DM can substantially reduce the progression to type 2 DM. Positron emission tomography (PET) can provide novel insight into in vivo aspects of peripheral tissue insulin resistance in skeletal muscle and adipose tissue. The goal of my research career is to use PET to examine mechanisms for reversibility of insulin resistance within a paradigm of intervention-based clinical trials that involve insulin resistant subjects as compared to appropriately matched volunteers. The objectives of this research proposal are: 1) To use PET imaging of skeletal muscle in lean subjects, in combination with an exercise program, to test the hypothesis that exercise training improves skeletal muscle blood flow, glucose transport, and glucose phosphorylation. These results will ultimately be used as preliminary data for a future R01 in order to determine: a) if the effects of exercise on skeletal muscle blood flow and glucose metabolism in obese subjects with and without type 2 DM are different from the effects in lean subjects and b) if the effects of exercise on skeletal muscle insulin resistance in obesity and type 2 DM are different from the effects of weight loss alone, which appears, from our preliminary data, to improve glucose transport/phosphorylation. 2) To use the combined PET/CT scanner, which provides accurate co-registration of anatomy determined with computed tomography (CT) and metabolism (PET), for quantitative determinations of region-specific adipose tissue metabolism in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Initially, lean subjects will be studied to test the hypothesis that region-specific variations in adipose tissue [18F]FDG uptake exist in vivo. This study is an extension of my prior training in PET imaging in insulin resistance and diverges from the area of skeletal muscle metabolism (my mentor's primary area of research) to adipose tissue metabolism. I plan to use this technique in future R01 applications to: a) provide further insight into the contribution of adipose tissue to total body glucose metabolism, b) determine if there are differences in adipose tissue [18F]FDG metabolism in lean, obese, and type 2 DM subjects, and c) determine the effects of various pharmacologic and clinical interventions on adipose tissue metabolism and in relation to muscle.
