The dynamic property of glucagon secretion in response to blood glucose--analysis with the aid of the control theory using an artificial endocrine pancreas

Abstract

The precise dynamic property of glucagon secretion in response to glucose concentration has not yet been elucidated, since in in vitro studies using pancreatic islets, the co-existence of pancreatic B cells modifies the mode of glucagon secretion, and in vivo studies, the exogenous insulin administration greatly affects pancreatic A cell function. In this study, to clarify the dynamic property of glucagon secretion in response to glucose concentration and the ability of glucagon to raise hepatic glucose production, an artificial endocrine pancreas was employed as a research tool. Our originally developed artificial endocrine pancreas prepared the glucagon and/or glucose infusion algorithm as the counterregulatory system. The principle of glucagon and glucose infusion algorithm is set as the proportional plus derivative modes of action to blood glucose concentration with time delay constant, as follows; Gn.I.R.(t) = Gp[BGp - BG(t - tau)] + Gd[-delta BG(t - tau)] + Gc G.I.R.(t) = Cp[BGp - BG(t - tau)] + Cd[-delta BG(t - tau)] where Gn.I.R.(t) and G.I.R.(t) are glucagon infusion rate and glucose infusion rate, respectively. BGp is the projected value of blood glucose concentration, and BG(t) and delta BG are blood glucose concentrations and the rate of change in blood glucose concentration at time t respectively. Gp and Gd are coefficients for glucagon infusion, and Cp and Cd are those for glucose infusion. Gc is the constant for basal glucagon supplementation. tau(min) is the time delay constant for glucagon and glucose infusion. In a depancreatized dog, the blood glucose concentration was maintained at the normoglycemic level with intraportal insulin infusion using this artificial endocrine pancreas for at least one hour, then hypoglycemia was induced by iv bolus insulin injection (0.1 U/kg). Glucagon was infused intraportally or glucose was infused into the peripheral vein when the counterregulatory system was operated according to each of these algorithm by variously changing the parameters. In the intraportal glucagon infusion algorithm, with the optimal parameters based on proportional plus derivative modes of action with a 10-min time delay (Gp/Gd/Gc/tau = 0.2/0.4/0.6/10), both the blood glucose response curves and plasma glucagon profiles simulated those seen in normal dogs. On the other hand, glucagon infusion based only on the proportional action failed to simulate the blood glucose response and plasma glucagon profile of normal dogs. When glucose was infused on the basis of the proportional action with a 20-min time delay (Cp/Cd/tau - 0.2/0/20), the insulin-induced hypoglycemia in depancreatized dogs could be restored to normoglycemia in the sa