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EFFECTS OF OBESITY ON MUSCLE FFA UTILIZATION

Principal Investigator: KELLEY, DAVID E.

Obesity is a major public health concern due in part to the strong associations between obesity, insulin resistance and co-morbidities of hypertension, diabetes, dyslipidemia and atherosclerosis. Our clinical investigations have focused upon patterns of fatty acid metabolism in skeletal muscle of obese individuals and the potential relation to insulin resistance and regional patterns of fat distribution. We find that in obesity, skeletal muscle has reduced efficiency for oxidation of fatty acids during fasting conditions yet essentially normal rates of uptake of plasma FFA and therefore, we postulate this leads to increased fat deposition within skeletal muscle. Unfortunately, diet induced weight loss while effective to reduce visceral and generalized adiposity, had little effect on patterns of fatty acid metabolism in skeletal muscle and did not improve the reduced activity of muscle CPT and other oxidative enzymes which we find in muscle of obese individuals. We posit that inefficiency in the oxidation of fatty acids, likely due to compromised transport of fatty acids into mitochondria, leads to increased fat deposition within muscle and thereby sets the conditions for lipid induced insulin resistance of obesity. In this application for renewed support, we propose to study the efficacy of exercise (4 months aerobic exercise) alone and in combination with a weight loss program (the very low calorie diet we have used previously without exercise) for improving the capacity of skeletal muscle for the utilization of fatty acids in obesity. A cohort of lean controls will be studied before and following the exercise program. At baseline and following intervention, fatty acid uptake will be measured using leg balance and stable isotope methodology together with regional indirect calorimetry studies of substrate oxidation. Insulin sensitivity will be measured using the glucose clamp method. We will assess the functional capacity of the respiratory chain to better delineate where an obesity-related impairment of fat oxidation occurs. Muscle lipid content will be ascertained by lipid extraction and quantitative microscopy. Thus, using biochemical analysis of muscle, physiologic studies of substrate kinetics, and assessments of muscle composition, we will evaluate patterns of fatty acid uptake, oxidation and storage in obesity and the efficacy of exercise for improving fatty acid metabolism by skeletal muscle.

TYPE 2 DIABETES IN YOUTH: BETA CELL PRESERVATION

Principal Investigator: ARSLANIAN SILVA A.

Investigators from Children’s Hospital of Pittsburgh and the University of Pittsburgh have been selected to participate in this multi-center, 7.5 year clinical trial for the treatment of type 2 diabetes mellitus in children (T2DM). The group of investigators from Pittsburgh, led by Dr. Silva Arslanian brings together a long-standing tradition of expertise in: 1) childhood diabetes, 2) in investigating insulin resistance and secretion in children, 3) in behavioral medicine and lifestyle intervention for childhood obesity (Drs. Marcus and Vinditti), 4) in physical activity and lifestyle interventions (Drs. Kriska and Aaron), 5) in epidemiology of chronic disease and large intervention trials of obesity, type 2 diabetes and cardiovascular disease, and 6) in recruiting for large intervention trials (Janet Bonk). The PI, Silva Arslanian, M.D., has been at the forefront of the "emerging epidemic" of type 2 diabetes in children. Our proposal will investigate intervention strategies in youth with T2DM with the objective of delaying beta-cell deterioration and preserving beta-cell function. To this aim we propose to use a randomized clinical trial design with 3 arms: conventional care, behavioral lifestyle and risk management intervention, and behavioral lifestyle intervention combined with dual-agent insulin sensitizing therapy. Measures of beta-cell function and insulin resistance will be the primary outcome of interest. Urinary albumin excretion and carotid artery intima-media thickness will be the secondary outcomes of interest. We also propose that this RFA incorporate ancillary studies. A comprehensive approach to therapeutic interventions in children with type 2 diabetes mellitus will form the basis for prevention of adult morbidity and mortality starting early in childhood.




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