The hepatic extraction of insulin in normal man was evaluated by kinetic analysis of peripheral insulin behavior in the plasma following stimulation of endogenous insulin secretion. Prehepatic insulin production was determined by deconvolution of plasma connecting peptide behavior (C-peptide) and hepatic extraction of the secreted insulin determined with a three-compartment model for hepatic, vascular, and extravascular plasma spaces. Three dosages of oral glucose (10, 25, and 100 g) administered to normal volunteers resulted in 1.8 +/- 0.5, 2.7 +/- 1.1, and 7.2 +/- 1.6 U endogenous insulin secretion, respectively. Total hepatic exposure to insulin exceeded the endogenous secretion due to recycling to the liver from the systemic circulation. Decreasing insulin extraction by the liver (67-53-42%) in the presence of increasing insulin exposure (2.6-4.4-13.2 U) was observed during the dose-response to glucose. The rates of hepatic insulin extraction observed with arginine (58 +/- 9% with 3.2 U), and a normal meal (50 +/- 9% with 7.6 U) were intermediate between the extremes seen with the 10- and 100-g glucose challenge. These results quantitate hepatic exposure of insulin in man during differing stimuli of endogenous insulin secretion, and demonstrate reduced fractional hepatic extraction with increasing insulin exposure.