The development of a counterregulatory system for an artificial endocrine pancreas--invention of glucose and glucagon infusion algorithms

Abstract

To accomplish an artificial endocrine pancreas system by adding a glucose and glucagon infusion mechanism in the artificial beta cell developed originally in the First Department of Medicine, Osaka University Medical School, glucose and glucagon infusion algorithms were invented.The principle of glucose or glucagon infusion algorithm is determined as the proportional plus derivative modes of action to blood glucose concentration with a time delay constant, as follows : GIR (t) = Cp [BGp - BG (t-T)] + Cd [-_??_BG (t-T)]GnIR (t) = Gp [BGp - BG (t-T)] + Gd [-ABG (t-T)] + Gc where GIR (t) and GnIR (t) are the glucose infusion rate (mg·kg-1min 1) and glucagon infusion rate (ng.kg-1.min-1), respectively. BGp is the projected value of blood glucose concentration (mg/100ml), and BG (t) and _??_BG (t) are blood glucose concentration at time t (mg/ 100ml) and the rate of change in blood glucose concentration at time t (mg·100ml-1), respectively. Cp and Cd are coefficients for glucose infusion, and Gp and Gd are those for glucagon infusion. Gc is the constant for basal glucagon infusion supplementation. T (min) is the time delay constant for glucose and glucagon infusion.The validation of these algorithms were attempted in depancreatized dogs. In dogs, hypoglycemias were induced by iv bolus insulin injections, then a counterregulatory system was operated according to each of these algorithms.The following results were obtained : 1) When glucose was infused on the basis of the proportional action with a 20-min time delay (Cp/Cd/T = 0.2/0/20), the insulin-induced hypoglycemia in depancreatized dogs could be restored to normoglycemia in the same manner as seen in normal dogs.2) A speedier and less fluctuating restoration to normoglycemia could be obtained when the glucose was infused on the basis of a proportional plus derivative mode of action with a 4-min time delay (Cp/Cd/T = 0.5/0.5/4).3) In glucagon infusion algorithm, with the optimal parameters based on proportional plus derivative modes of action with a 10-min time delay (Gp/Gd/Gc/T = 0.2/0.4/0.4/10), both the blood glucose response curves and plasma glucagon profiles simulated perfectly those seen in normal dogs.4) When glucagon was infused on the basis of proportional plus derivative modes of action without the time delay (Gp/Gd/Gc/T = 0.5/0.5/0.4/0), hypoglycemias rarely occurred in spite of iv insulin injections with the least glucagon infusion amount.These results clearly indicate that an artificial endocrine pancreas system characterized with glucose or glucagon infusion algorithm constitutes a clinically useful device not only as a safety control against hypoglycemia, but it also enables adaptive and optimal glycemic controls. In addition, by applying these algorithms, an artificial endocrine pancreas system becomes a powerful research tool for such investigations as the dynamic property of the pancreatic a cell in glucagon secretion against blood glucose, the analysis of the effects of hormones on the glucoregulatory system and for the glucose clamp method.