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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24DK002782-05
Application #
6690704
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2000-04-01
Project End
2004-07-01
Budget Start
2004-01-01
Budget End
2004-07-01
Support Year
5
Fiscal Year
2004
Total Cost
$42,911
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kelley, David E; Kuller, Lewis H; McKolanis, Therese M et al. (2004) Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in type 2 diabetes. Diabetes Care 27:33-40
He, Jing; Goodpaster, Bret H; Kelley, David E (2004) Effects of weight loss and physical activity on muscle lipid content and droplet size. Obes Res 12:761-9
Williams, Katherine V; Bertoldo, Alessandra; Kinahan, Paul et al. (2003) Weight loss-induced plasticity of glucose transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes. Diabetes 52:1619-26
Williams, Katherine V; Bertoldo, Alessandra; Mattioni, Bruno et al. (2003) Glucose transport and phosphorylation in skeletal muscle in obesity: insight from a muscle-specific positron emission tomography model. J Clin Endocrinol Metab 88:1271-9
Goodpaster, Bret H; Katsiaras, Andreas; Kelley, David E (2003) Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity. Diabetes 52:2191-7
Kelley, David E; McKolanis, Therese M; Hegazi, Refaat A F et al. (2003) Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab 285:E906-16
Kelley, D E; Williams, K V; Price, J C et al. (2001) Plasma fatty acids, adiposity, and variance of skeletal muscle insulin resistance in type 2 diabetes mellitus. J Clin Endocrinol Metab 86:5412-9