Nonlinear Mixed Effects Modeling of Glucagon Kinetics in Healthy Subjects

Abstract

Objective: To date, the lack of a model of glucagon kinetics precluded the possibility of estimating and studying glucagon secretion in vivo, e.g., using deconvolution, as done for other hormones like insulin and C-peptide. Here, we used a nonlinear mixed effects technique to develop a robust population model of glucagon kinetics, able to describe both the typical population kinetics (TPK) and the between-subject variability (BSV), and relate this last to easily measurable subject characteristics. Methods: Thirty-four models of increasing complexity (variably including covariates and correlations among random effects) were identified on glucagon profiles obtained from 53 healthy subjects, who received a constant infusion of somatostatin to suppress endogenous glucagon production, followed by a continuous infusion of glucagon (65 ng/kg/min). Model selection was performed based on its ability to fit the data, provide precise parameter estimates, and parsimony criteria. Results: A two-compartment model was the most parsimonious. The model was able to accurately describe both the TPK and the BSV of model parameters as function of body mass and body surface area. Parameters were precisely estimated, with central volume of distribution V1 = 5.46 L and peripheral volume of distribution V2 = 5.51 L. The introduction of covariates resulted in a significant shrinkage of the unexplained BSV and considerably improved the model fit. Conclusion: We developed a robust population model of glucagon kinetics. Significance: This model provides a deeper understanding of glucagon kinetics and is usable to estimate glucagon secretion in vivo by deconvolution of plasma glucagon concentration data.