DIABETES TECHNOLOGY & THERAPEUTICS Volume 8, Number 6, 2006 © Mary Ann Liebert, Inc. Dynamic Modeling of Free Fatty Acid, Glucose, and Insulin: An Extended “Minimal Model” ANIRBAN ROY, M.S., and ROBERT S. PARKER, Ph.D. ABSTRACT Background: The mathematical models for patients with diabetes proposed in the literature since the late 1970s are mainly glucocentric (glucose-based); hence, the contribution of free fatty acid (FFA) metabolism in the body and its glucose–insulin interactions have been largely ig- nored. However, approximately 90% of the muscle energy is derived from FFA metabolism when the body is at rest. Furthermore, significant interactions exist among FFA, glucose, and insulin. With the long-term goal of developing a closed-loop glucose control system, a model of the ma- jor energy-providing substrate dynamics is required. Methods: The Bergman minimal model was extended to include plasma FFA dynamics, and its interaction with glucose and insulin dynamics, with a primary focus on patients with Type 1 diabetes. Differential equations were developed for plasma FFA concentrations and “remote” FFA effects on glucose uptake, as well as “remote” insulin effects on plasma FFA concentrations. Parameters for the model were estimated from experimental data provided in the scientific lit- erature. Results: The minimal model was extended in order to capture three major metabolic aspects: the antilipolytic effect of insulin; the lipolytic effect of prolonged hyperglycemia; and the im- pairing effect of FFA on glucose uptake rate. The dynamic fit of glucose, FFA, and insulin pro- files is consistent with published data. Conclusions: The extended minimal model successfully captured the plasma FFA concentra- tion behavior, the plasma insulin and glucose concentrations, and the physiological interactions that exist among these species. This more comprehensive description of energy-providing sub- strate dynamics may provide a novel simulation test-bed for analysis of patients with insulin- dependent diabetes and controller design. 617 INTRODUCTION I N THE CONTEXT OF METABOLISM, the pancreas is a very important organ in the human body. The -cells present in the pancreas secrete in- sulin in order to facilitate glucose uptake by the body tissues as a substrate for energy. Mal- functioning of these -cells is the cause of dia- betes, which is increasingly prevalent around the world. In the year 2002, there were about 18 million diabetic patients in the United States alone, and the total cost of diabetes in the same year was approximately $132 billion. 1 Significant glucose variation is a key charac- teristic of diabetes. Prolonged hyperglycemia can cause chronic complications that can lead Department of Chemical and Petroleum Engineering, University of Pittsburgh, Pittsburgh, Pennsylvania.