IVGTT glucose minimal model covariate selection by nonlinear mixed-effects approach

Abstract

Population approaches, traditionally employed in pharmacokinetic-pharmacodynamic studies, have shown value also in the context of glucose-insulin metabolism models by providing more accurate individual parameters estimates and a compelling statistical framework for the analysis of between-subject variability (BSV). In this work, the advantages of population techniques are further explored by proposing integration of covariates in the intravenous glucose tolerance test (IVGTT) glucose minimal model analysis. A previously published dataset of 204 healthy subjects, who underwent insulin-modified IVGTTs, was analyzed in NONMEM, and relevant demographic information about each subject was employed to explain part of the BSV observed in parameter values. Demographic data included height, weight, sex, and age, but also basal glycemia and insulinemia, and information about amount and distribution of body fat. On the basis of nonlinear mixed-effects modeling, age, visceral abdominal fat, and basal insulinemia were significant predictors for SI (insulin sensitivity), whereas only age and basal insulinemia were significant for P2 (insulin action). The volume of distribution correlated with sex, age, percentage of total body fat, and basal glycemia, whereas no significant covariate was detected to explain variability in SG (glucose effectiveness). The introduction of covariates resulted in a significant shrinking of the unexplained BSV, especially for SI and P2 and considerably improved the model fit. These results offer a starting point for speculation about the physiological meaning of the relationships detected and pave the way for the design of less invasive and less expensive protocols for epidemiological studies of glucose-insulin metabolism.