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Integrated model of hepatic and peripheral glucose regulation for estimation of endogenous glucose production during the hot IVGTT

Resource Facility for Population Kinetics, Department of Bioengineering, University of Washington, Seattle, Washington

Submitted 4 February 2004 ; accepted in final form 14 December 2004

We have developed a new model to describe endogenous glucose kinetics during a labeled (hot) intravenous glucose tolerance test (IVGTT) to derive a time profile of endogenous glucose production (EGP). We reanalyzed data from a previously published study (P. Vicini, J. J. Zachwieja, K. E. Yarasheski, D. M. Bier, A. Caumo, and C. Cobelli. Am J Physiol Endocrinol Metab 276: E285–E294, 1999), in which insulin-modified [6,6-²H₂]glucose-labeled IVGTTs (0.33 g/kg glucose) were performed in 10 normal subjects. In addition, a second tracer ([U-¹³C]glucose) was infused in a variable rate to clamp the endogenous glucose tracer-to-tracee ratio (TTR). Our new model describing endogenous glucose kinetics was incorporated into the two-compartment hot minimal-model structure. The model gave estimates of glucose effectiveness [1.54 ± 0.31 (SE) ml·kg^–1·min^–1], insulin sensitivity (37.74 ± 5.23 10⁴ dl·kg^–1·min^–1·µU^–1·ml), and a new parameter describing the sensitivity of EGP to the inhibitory effect of insulin (IC₅₀ = 0.0195 ± 0.0046 min^–1). The model additionally provided an estimate of the time course of EGP showing almost immediate inhibition, followed by a secondary inhibitory effect caused by infusion of insulin, and a large overshoot as EGP returns to its basal value. Our estimates show very good agreement with those obtained via deconvolution and the model-independent TTR clamp technique. These results suggest that the new integrated model can serve as a simple one-step approach to obtain metabolic indexes while also providing a parametric description of EGP.

hot minimal model; intravenous glucose tolerance test; mathematical modeling; insulin sensitivity

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