382d Dynamic Modeling and Analysis of Glucose and Fatty Acid Interactions In Skeletal Muscle Tissue

Baris U. Agar, Department of Chemical and Biological Engineering, Illinois Institute of Technology, 10 W. 33rd Street, Chicago, IL 60616, Ali Cinar, Chemical and Biological Engineering, Illinois Institute of Technology, 10 W. 33rd Street, Chicago, IL 60616, Emmanuel C. Opara, Department of Biomedical Engineering, Illinois Institute of Technology, 10 W. 32nd Street, Chicago, IL 60616, and Gary Reznik, Microbiology and Immunology Division, IIT Research Institute (IITRI), 10 W. 35th Street, Chicago, IL 60616.

A mathematical model of glucose and free fatty acid (FFA) utilization in skeletal muscle tissue has been developed. The effects of changes in plasma FFA concentration on the utilization of glucose, and the effects of changes in glucose concentration on the utilization of FFA have been investigated via sensitivity analysis tools to illustrate the competing nature of FFA and glucose as fuel sources for skeletal muscle tissue.

Diabetes is estimated to affect 21 million people in the United States and type 2 diabetes accounts for more than 90 percent of all diagnosed cases [1]. Several studies indicate that obesity is associated with an increased risk of type 2 diabetes [2, 3] and FFA levels are elevated in most obese subjects [4]. Increased FFA and intracellular lipid concentrations are the primary suspects for causing insulin resistance in liver and muscle tissue. Physiological elevations of plasma FFA inhibit insulin stimulated glucose uptake in a dose dependent fashion [4].

The effect of elevated FFA concentration on utilization of glucose is described by the glucose-fatty acid cycle hypothesis [5]. According to this hypothesis, glucose and FFA compete with each other to serve as an energy source. Elevation of plasma FFA levels inhibits glucose uptake, which leads to muscle cells with impaired sensitivity to insulin, a suspected cause of Type 2 diabetes. Experimental studies have shown glucose transport as the step at which FFA induces insulin resistance [6, 7]. Similarly, an increase in insulin mediated glucose utilization causes suppression of FFA oxidation [8, 9]. According to experimental studies, increased glucose utilization leads to an increase in cellular malonyl-CoA levels which may inhibit the transportation of fatty acyl-CoA into the mitochondria, the site of FFA oxidation [9].

The kinetic equations governing the rate of formation and disappearance of metabolites involved in skeletal muscle energy metabolism are constructed based on previous work by Dash and co-workers [10]. In addition, the kinetics of FFA transportation, its inhibition by malonyl-CoA formation and the effect of FFA on glucose transportation are formulated and the kinetic constants of the final model are updated based on experimental findings.

Simulation studies indicate that an increase in plasma FFA level alone is sufficient to increase FFA utilization significantly whereas increased level of insulin is necessary for plasma glucose to induce increased glucose utilization. A sensitivity analysis on plasma FFA concentration reveals that glucose disposal may decrease by %20 through a two-fold increase in plasma FFA levels. A bifurcation analysis tool is being developed to observe the stable and unstable steady states, to address steady state multiplicity and to aid in the sensitivity analysis of the system.

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