Abstract The liver plays a pivotal role in determining post- prandial insulin levels because it is responsible for the extraction of a large (approximately 50%) fraction of the newly secreted insulin by the pancreas. Evidence exists that hepatic insulin extraction is not constant during a meal, but is inhibited because of saturable receptor-mediated mecha- nisms and/or increase in hepatic blood flow. The aim of the present study was to exploit the ability of mathematical model simulation to shed light on the role of a variable hepatic insulin extraction during a meal. Mathematical models of insulin secretion and kinetics were coupled to provide predictions for the concentration of insulin in plas- ma following a meal under the assumptions of either a con- stant or a time-varying hepatic insulin clearance. Our results indicate that a 20% inhibition in hepatic clearance is able to remarkably enhance the plasma insulin level fol- lowing a meal. These results emphasise the need for simple and accurate methods to measure the time course of hepat- ic insulin extraction under nonsteady-state conditions. Key words Insulin secretion • Insulin kinetics • Hepatic insulin clearance • Model Introduction The insulin response following glucose ingestion is an important determinant of prandial glucose tolerance [1]. It must be recognised, however, that the amount of insulin reaching the systemic circulation is dependent not only on β-cell secretion, but also on hepatic insulin extraction. In fact, approximately half of the endogenously secreted insulin is removed from the portal blood by the liver [2]. Furthermore, as evidence has been produced that hepatic insulin extraction is inhibited after oral glucose adminis- tration [3–5], one may wonder what are the practical con- sequences of this phenomenon on the insulin rise observed postprandially. At present, a full answer cannot come from published data as no experimental techniques are available to manipulate insulin degradation in the liver and allow a comparison of the effects of a constant vs. a variable hepat- ic insulin clearance. While awaiting the conclusive “exper- imental data” answer, we thought that a quantitative insight on this issue could be obtained by exploiting math- ematical model simulation. In order to predict the time course of insulin concentration during a meal, the model of β-cell secretion developed by Toffolo et al. [6] was cou- pled with the three-compartment model of insulin kinetics proposed by Sherwin et al. [7]. Two simulations were per- formed assuming either a constant or a time-varying hepat- ic clearance. For each simulation run, a postprandial insulin concentration profile was generated. The simula- tion results indicate that a variable hepatic extraction can play a relevant role in the postprandial insulin profile. Methods Plasma insulin dynamics during a meal are the result of pancre- atic insulin secretion, first-pass extraction by the liver, and dis- Acta Diabetol (2007) 44:23–29 DOI 10.1007/s00592-007-0237-7 A. Caumo • I. Florea • L. Luzi Effect of a variable hepatic insulin clearance on the postprandial insulin profile: insights from a model simulation study ORIGINAL A. Caumo • I. Florea • L. Luzi () Unit of Nutrition and Metabolism Department of Medicine San Raffaele Scientific Institute Via Olgettina 60, I-20132 Milan, Italy E-mail: luzi.livio@hsr.it L. Luzi Faculty of Exercise Sciences Center “Physical Exercise for Health and Wellness” University of Milan, Italy Received: 30 January 2006 / Accepted in revised form: 11 October 2006 © 2007 The Authors 1 1 This is a “Springer Open Choice” article. Unrestricted non-com- mercial use, distribution and reproduction in any medium are per- mitted, provided the original author and source are credited.