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ENDOCRINE PHYSIOLOGY AND METABOLISM

Evaluation of quantitative models of the effect of insulin on lipolysis and glucose disposal

¹Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), Bethesda, Maryland; ²Department of Physiology, University of Southern California School of Medicine, Los Angeles, California; ³Clinical Endocrinology Branch, NIDDK, Bethesda, Maryland; and ⁴Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas

Submitted 15 May 2008 ; accepted in final form 5 August 2008

The effects of insulin on the suppression of lipolysis are neither fully understood nor quantified. We examined a variety of mathematical models analogous to the minimal model of glucose disposal (MMG) to quantify the combined influence of insulin on lipolysis and glucose disposal during an insulin-modified frequently sampled intravenous glucose tolerance test. The tested models, which include two previously published ones, consisted of separate compartments for plasma free fatty acids (FFA), glucose, and insulin. They differed in the number of compartments and in the action of insulin to suppress lipolysis that decreased the plasma FFA level. In one category of models, a single insulin compartment acted on both glucose and FFA simultaneously. In a second category, there were two insulin compartments, each acting on FFA and glucose independently. For each of these two categories, we tested 11 variations of how insulin suppressed lipolysis. We also tested a model with an additional glucose compartment that acted on FFA. These 23 models were fit to the plasma FFA and glucose concentrations of 102 subjects individually. Using Bayesian model comparison methods, we selected the model that best balanced fit and minimized model complexity. In the best model, insulin suppressed lipolysis via a Hill function through a remote compartment that acted on both glucose and FFA simultaneously, and glucose dynamics obeyed the classic MMG.

free fatty acids; insulin resistance; mathematical model