The effect of equal (1.1 +/- 0.1 g/kg body wt) amounts of glucose administered orally, or by peripheral intravenous or intraportal infusion on hepatic glucose uptake and fractional hepatic extraction of insulin and glucagon was studied in conscious dogs with chronically implanted Doppler flow probes on the portal vein and hepatic artery and catheters in the portal vein, hepatic vein, carotid artery, and superior mesenteric vein. Portal vein and hepatic vein plasma flow increased only after oral glucose administration. Arterial plasma glucose increased equally to 150-160 mg/100 ml after all three routes of glucose administration. Portal vein glucose was similar after oral (195 +/- 15 mg/100 ml) and intraportal glucose infusion (215 +/- 11 mg/100 ml) and significantly higher than after peripheral intravenous glucose. Hepatic glucose uptake after oral (68 +/- 4%) and intraportal glucose administration (65 +/- 7%) significantly exceeded that after peripheral intravenous glucose infusion (23 +/- 5%). The amount of insulin above basal presented to the liver during the 180 min after oral glucose was 7.6 +/- 1.3 U, 4.3 +/- 0.6 U after intraportal glucose, and 4.1 +/- 0.6 U after peripheral intravenous glucose. Hepatic extraction of insulin increased significantly after oral glucose (42 +/- 3 to 61 +/- 4%), but was unchanged after intraportal and peripheral intravenous glucose administration. When the portal vein glucose levels achieved during peripheral intravenous glucose infusion for 90 min were maintained by a subsequent 90-min intraportal glucose infusion, hepatic glucose uptake was significantly greater during the intraportal glucose infusion. Glucagon secretion was suppressed equally after oral glucose, intraportal glucose, and peripheral intravenous glucose administration; fractional hepatic extraction of that hormone, which was significantly less than that of insulin, was unchanged. These results indicate that hepatic glucose uptake is significantly greater after oral and intraportal glucose administration than after peripheral intravenous glucose infusion. This difference is not simply related to the amount of glucose or insulin presented to the liver and the increased hepatic glucose uptake did not depend solely upon the augmented fractional hepatic extraction of insulin. Hepatic extraction of insulin and hepatic glucose uptake appear to be regulated independently.