Analysis of Glucose Responsive Glucagon Therapeutics using Computational Models of the Glucoregulatory System.

Abstract

Glucose-responsive glucagon (GRG) therapeutics are a promising technology for reducing the risk of severe hypoglycemia as a complication of diabetes mellitus. Herein, the performance of candidate GRGs in the literature by modeling the kinetics of activation and connecting them as input into physiological glucoregulatory models is evaluated and projected the two distinct GRG designs, experimental results reported in Wu etal. (GRG-I) and Webber etal. (GRG-II) is considered. Both are evaluated using a multi-compartmental glucoregulatory model (IMPACT) and used to compare in-vivo experimental data of therapeutic performance in rats and mice. For GRG-I and GRG-II, the total integrated glucose material balances are overestimated by 41.5% ± 14% and underestimated by 24.8% ± 16% compared to in-vivo time-course data, respectively. These large differences to the relatively simple computational descriptions of glucagon dynamics in the model, which underscores the urgent need for improved glucagon models is attributed. Additionally, therapeutic insulin and glucagon infusion pumps are modeled for type 1 diabetes mellitus (T1DM) human subjects to extend the results to additional datasets. These observations suggest that both the representative physiological and non-physiological models considered in this work require additional refinement to successfully describe clinical data that involve simultaneous, coupled insulin, glucose, and glucagon dynamics.