A Model of Glucose-insulin Homeostasis in Man that Incorporates the Heterogeneous Fast Pool Theory of Pancreatic Insulin Release

Abstract

Current physiologic knowledge about glucose-insulin homeostasis in liver, brain, pancreas, kidney, peripheral tissues, and central vascular organs has been synthesized to form a whole-system mathematical model of glucose metabolism in normal, ideal man. In addition to data of other workers, results from more than 100 intravenous glucose tolerance tests, including variable dosage, variable duration of infusion, and double pulse studies, were used to determine model structure and parameters. Model and clinical testing have focused particularly on the fast phase of insulin response to vascular glucose. The model incorporates blood circulation and equilibration of substances between vascular and interstitial spaces, and it assumes constant fractional clearance of insulin by liver and kidney. Studies using a double pulse of glucose suggest that the time derivative of glucose level is not the sole or predominant influence on fast phase insulin release, but that preinfusion glucose level and/or previous glucose exposure of the pancreas are also important. Variable dosage glucose studies suggest that the amount of insulin released during the fast phase rather than the insulin release rate is regulated by the glucose level. A two-pool, heterogeneous threshold mechanism for beta cell response to glucose is presented that is compatible with the clinical results.