The dual tracer time-varying volume method for measuring hepatic glucose release on nonsteady state: theoretical and simulation results

Measurement of hepatic glucose release in nonsteady state is difficult and experimental approaches have been developed in order to circumvent Steele's model inadequacy. Recently, a resurgence of interest in the time-varying volume method developed by Issekutz has taken place. Issekutz's approach assumes that the volume of Steele's model is not constant but time-varying and that its time course can be measured by infusing two tracers with different patterns. The time-varying volume is then substituted into Steele's equation and hepatic glucose release is estimated. The aim of this study was to analyze some basic aspects of Issekutz's method and to determine the accuracy of its estimate of hepatic glucose release. A theoretical analysis showed that the time-varying volume measured by Issekutz's approach is not unique but depends on the format of administration of the two tracers. In addition, such a volume allows an accurate estimate of hepatic glucose release if one of the two tracers is infused in such a way that its specific activity is maintained perfectly constant during the experiment. Since it is impossible to achieve a perfect clamp of specific activity, we also evaluated the performance of Issekutz's approach in more realistic experimental conditions which were reproduced by resorting to computer simulation. We simulated a euglycaemic clamp with insulin rising from basal to a plateau of approximately 40 μU/ml and then returning to basal. Nonsteady-state glucose kinetics were described by a previously validated two-compartment model while the time course of hepatic glucose release was derived from the literature. Both noise-free and noisy experimental conditions were simulated. We showed that the degree of accuracy of Issekutz's approach is very good and better than the one associated with the hot-ginf method. On the other hand, the major problem with Issekutz's approach is the sensitivity of the volume estimate tot he measurement noise, which may limit its applicability in practice. In conclusion, we elucidated the theoretical grounds of Issekutz's approach and assessed its performance during nonsteady state in a realistic scenario using computer simulation.