Estimation of β-Cell Sensitivity From Intravenous Glucose Tolerance Test C-Peptide Data: Knowledge of the Kinetics Avoids Errors in Modeling the Secretion

Abstract

Parametric models of insulin secretion are used to measure indexes of beta-cell function from plasma C-peptide concentration during an intravenous glucose tolerance test (IVGTT). Since the models have been usually assessed against plasma C-peptide data, both secretory and kinetic parameters need to be simultaneously estimated. However, undesired compensations between the two sets of parameters may arise. In this study, in order to evaluate IVGTT insulin secretion models, we have analyzed IVGTT data from seven normal subjects for whom individual C-peptide kinetics were known from a separate experiment. Three different beta-cell models have been examined: the minimal model M1 (Diabetes 37:223-231, 1988); a variation of a published model, M2 (Math Biosci 27:319-332, 1975); and a new one, M3. A two-compartment model was used to describe C-peptide kinetics. The results suggest the inadequacy of M1 since kinetic parameter estimates were consistently biased versus the known individual values, and systematic errors were present in the prediction of C-peptide data when kinetic parameters were fixed to the known individual values. M2 performs better than M1 since it reproduces C-peptide data satisfactorily when the individually known description of the kinetics is adopted. M3 retains the second-phase description of M2 but improves the description of first-phase release. M3 is thus proposed to reconstruct the insulin secretion time course and to estimate parameters of first- and second-phase sensitivity to glucose. We also show the robustness of M3, i.e., standard values of C-peptide kinetic parameters can be used when individual values are not available without a loss of accuracy in the estimated secretion parameters. Finally, the shortcomings of using a simplified single-compartment description of C-peptide kinetics are discussed.

Heritability of model-derived parameters of beta cell secretion during intravenous and oral glucose tolerance tests: a study of twins

“…In a standard IVGTT analysed with minimal models, sampling is prolonged until 180-240 min, and glucose thresholds and basal insulin secretion rates are based on the levels attained at the end of the test [13,14]. Thus, glucose threshold and basal insulin secretion in the minimal model analysis of the IVGTTs included in the present study were higher than they might have been if sampling had been continued for an additional 120-180 min.…”

“…This model is similar to the one proposed by us for C-peptide during hyperglycaemic clamp [11], which, in turn, was based primarily on the minimal model introduced by Toffolo et al for C-peptide during IVGTT [13] (described in the Appendix). Both readily releasable insulin (RRI; the first peaking phase of insulin secretion during IVGTT; pmol·l −1 ) and sigma (beta cell sensitivity to glucose during the second phase of insulin secretion;…”

“…The analysis of the glucose and insulin curves during the IVGTT follows the general strategy proposed by Toffolo et al [13] with some slight changes. Since insulin kinetics cannot be computed with the experimental design employed in the present paper and, as opposed to C-peptide [22], cannot be inferred on the basis of population-derived parameters, it is assumed to be monocompartmental and all parameters of insulin secretion are normalised to the insulin distribution volume, which remains undetermined.…”

“…In the last two decades, mathematical modelling of betacell-derived hormone concentration over time has progressed considerably, enabling one to safely distinguish between early and late phases of insulin secretion under experimental reference conditions, such as IVGTT [12][13][14] and hyperglycaemic clamp [11]. Recently, we introduced a parsimonious model of C-peptide secretion during OGTT as a tool for the physiological assessment of beta cell function [15].…”

Multiscale modelling of insulin secretion during an intravenous glucose tolerance test

“…Minimal models are useful tools for the study of IVGTT data by estimating parameters from model fitting to the observed data [3][4][5], and can provide a fuller picture of b-cell function than the AIR index, in particular when based on C-peptide measurements [5,6]. These models must be fairly simple to allow parameter identification, but should at the same time reflect truthfully the underlying biology down to the cellular events underlying insulin secretion.…”