The ability to accurately quantify indexes of the individual role of glucose (GE(L)) and insulin (S(I)(L)) in the suppression of endogenous glucose production (EGP) would improve the understanding of liver metabolism. Measuring these indexes during an IVGTT by minimal modeling of tracer labeled and unlabeled glucose data is often unreliable, possibly due to an inadequate description of EGP included in the Minimal Model. Moreover, a validation of the assumptions of the Minimal Model on EGP data has never been done. Recently, Krudys et al. (Krudys KM, Dodds MG, Nissen SM, Vicini P. Am J Physiol Endocrinol Metab 288: E1038-E1046, 2005) have proposed a PK/PD (pharmacokinetic/pharmacodynamic) model of the EGP profile that occurs during an intravenous glucose tolerance test (IVGTT); however, this model has also not been validated. The aim of this study was thus to test the Minimal Model, the PK/PD model, and six alternative EGP descriptions on recent model-independent EGP data of 20 subjects obtained with a triple-tracer meal protocol. Model performance was compared in terms of data fit, precision of the estimated parameters, and physiological plausibility. Neither the PK/PD nor the traditional Minimal Model were able to accurately describe EGP data or provide reliable estimates of the indexes. In contrast, one of the new models performed best by showing a good fit and providing accurate and precise estimates of hepatic sensitivity indexes: GE(L) = 0.013 +/- 0.001 dl x kg(-1) x min(-1); S(I)(L) = 5.34 +/- 0.47 10(-4) dl x kg(-1) x min(-1) per microU/ml (42 and 34%, respectively, of total sensitivity indexes GE(TOT) and S(I)(TOT)). Although this model requires further validation, it has the potential to improve our understanding of the role of the liver in pathophysiological states.