The integrated glucose insulin minimal model: An improved version

• Published in: European journal of pharmaceutical sciences Vol. 134; pp. 7 - 19
• Main Authors: Ibrahim, Moustafa M.A., Largajolli, Anna, Karlsson, Mats O., Kjellsson, Maria C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.06.2019
• Subjects: Blood Glucose - biosynthesis; Blood Glucose - metabolism; Diabetes Mellitus, Type 2; Glucose - biosynthesis; Glucose - metabolism; Glucose effectiveness; Glucose Tolerance Test; Healthy Volunteers; Humans; Insulin - blood; Insulin Resistance; Insulin sensitivity; Liver; Mathematics; Minimal model; Models, Biological; Nonlinear mixed effects; NONMEM; Nonlinear mixed effects; Minimal model; Insulin sensitivity; Glucose effectiveness; NONMEM
• ISSN: 0928-0987; 1879-0720; 1879-0720
• DOI: 10.1016/j.ejps.2019.04.010

This paper describes the improved integrated minimal model for healthy subjects and patients with type 2 diabetes and the work leading up to this model. The original integrated minimal model characterizes simultaneously glucose and insulin following intravenous glucose tolerance test (IVGTT) in healthy subjects and provides apart from estimates of indices for insulin sensitivity (Si) and glucose effectiveness (SG), also full simulation capabilities. However, this model was developed using IVGTT data of total glucose and consequently, the model cannot separate hepatic glucose production from glucose disposal. By fitting the original integrated minimal model to IVGTT data of labelled and total glucose, we show that all parameter estimates of the glucose sub-model were significantly different between the fits, in particular, SG, which was ~3 fold higher with total, compared to labelled glucose. In addition, the time profiles of hepatic glucose production, obtained from the model, were unphysiological in most subjects. To correct these flaws, we developed the improved integrated minimal model based on the non-integrated, two-compartment minimal model. The improved integrated minimal model showed physiologically plausible dynamic time profiles of hepatic glucose production and all parameter estimates were compatible with those reported in original publication of the non-integrated minimal model. The integrated minimal model offers the benefits of the original integrated minimal model with simulation capabilities, in presence of endogenous insulin, combined with the benefits of the non-integrated minimal model, which accurately estimates the clinical indices of insulin sensitivity and glucose effectiveness. In addition, the improved integrated minimal model describes, apart from healthy subjects, also patients with type 2 diabetes. [Display omitted]