Hepatic and Extrahepatic Insulin Clearance Are Differentially Regulated: Results From a Novel Model-Based Analysis of Intravenous Glucose Tolerance Data

Abstract

Insulin clearance is a highly variable and important factor that affects circulating insulin concentrations. We developed a novel model-based method to estimate both hepatic and extrahepatic insulin clearance using plasma insulin and C-peptide profiles obtained from the insulin-modified frequently sampled intravenous glucose tolerance test. Data from 100 African immigrants without diabetes (mean age 38 years, body weight 81.7 kg, fasting plasma glucose concentration 83 mg/dL, and fasting insulin concentration 37 pmol/L) were used. Endogenous insulin secretion (calculated by C-peptide deconvolution) and insulin infusion rates were used as inputs to a new two-compartment model of insulin kinetics and hepatic and extrahepatic clearance parameters were estimated. Good agreement between modeled and measured plasma insulin profiles was observed (mean normalized root mean square error 6.8%), and considerable intersubject variability in parameters of insulin clearance among individuals was identified (the mean [interquartile range] for hepatic extraction was 25.8% [32.7%], and for extrahepatic insulin clearance was 20.7 mL/kg/min [11.7 mL/kg/min]). Parameters of insulin clearance were correlated with measures of insulin sensitivity and acute insulin response to glucose. The method described appears promising for future research aimed at characterizing variability in insulin clearance and the mechanisms involved in the regulation of insulin clearance.

Trial registration: ClinicalTrials.gov NCT00001853.

Figure 1

Graphical representation of the mathematical model described by Eqs. 1 and 2. The HPF rate used in the equations is the combined plasma flow to the liver from the portal vein and the hepatic artery.

Figure 2

Measured profiles for plasma glucose (A), insulin (B), and C-peptide (C) concentrations. The calculated ISR is shown in the inset of C; only the first 40 min are shown to highlight the region where insulin secretion is highest. In panel D, the total amount of insulin secreted and infused over the intervals 0–5 min and 20–25 min are shown. Values shown are the mean ± SD.

Figure 3

Comparison of modeled and measured insulin profiles. A: Mean ± SD for measured (dots and error bars) and modeled (line and shaded region) values. B–E: Profiles for four representative participants having different plasma insulin profiles and different parameter estimates for hepatic and peripheral clearance.

Figure 4

Distribution of parameter values and the relationship between the clearance for endogenously secreted insulin (CL_portal) and measures of insulin sensitivity and release. Panels A–E show the distribution of values for the various model parameters, with the y-axis showing the number of subjects in each range of parameter values. Panel F shows the relationship between FE_L and CL_P in the population. Panels G and H show the relationships between CL_P and S_I (panel G) and CL_portal and AIR_g (panel H); units for S_I are 10⁻⁴/(pmol/L)/min and units for AIR_g are pmol/L ⋅ min. Regression relationships were obtained using either linear regression (panel G) or nonlinear regression with a power function (AIR_g = β₁ ⋅ CL_portal^β2).