The liver plays a pivotal role in determining postprandial 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 mechanisms 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 plasma following a meal under the assumptions of either a constant 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 following a meal. These results emphasise the need for simple and accurate methods to measure the time course of hepatic insulin extraction under nonsteady-state conditions.