THE DUAL TRACER TIME-VARYING VOLUME METHOD FOR MEASURING HEPATIC GLUCOSE-RELEASE IN 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 circumven t Steele's model inadequacy. Recently, a resurgence of interest in the time-varying volume method developed by Issekutz has taken place. Iss ekutz's approach assumes that the volume of Steele's model is not cons tant but time-varying and that its time course can be measured by infu sing two tracers with different patterns. The time-varying volume is t hen 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 hep atic glucose release. A theoretical analysis showed that the time-vary ing volume measured by Issekutz's approach is not unique but depends o n 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 i mpossible to achieve a perfect clamp of specific activity, we also eva luated the performance of Issekutz's approach in more realistic experi mental conditions which were reproduced by resorting to computer simul ation. We simulated a euglycaemic clamp with insulin rising from basal to a plateau of approximately 40 mu U/ml and then returning to basal. Nonsteady-state glucose kinetics were described by a previously valid ated two-compartment model while the time course of hepatic glucose re lease was derived from the literature. Both noise-free and noisy exper imental conditions were simulated. We showed that the degree of accura cy of Issekutz's approach is very good and better than the one associa ted with the hot-ginf method. On the other hand, the major problem wit h Issekutz's approach is the sensitivity of the volume estimate to the measurement noise, which may limit its applicability in practice. In conclusion, we elucidated the theoretical grounds of Issekutz's approa ch and assessed its performance during nonsteady state in a realistic scenario using computer simulation.