The effects of hyperinsulinemia, hyperglycemia, and the route of glucose administration on total glucose utilization and on net splanchnic glucose exchange were studied in 20 normal volunteers with the hepatic venous catheter technique. Euglycemic hyperinsulinemia [induced by a priming plus continuous infusion of insulin resulting in plasma insulin levels of 400-1200 muunits (international)/ml and a variable glucose infusion] caused a 5- to 6-fold increase above basal in total glucose turnover. However, net splanchnic glucose uptake (0.5 +/- 0.2 mg/kg per min) accounted for only 4-5% of total glucose utilization. When hyperglycemia (223 +/- 1 mg/dl) was induced in addition to hyperinsulinemia by the intravenous infusion of glucose, splanchnic glucose uptake increased 100% to 1.0-1.1 mg/kg per min but was still responsible for only 10-14% of total glucose utilization. In other studies hyperglycemia (223 +/- 2 mg/dl) was maintained constant by a variable intravenous infusion of glucose for 4 hr and oral glucose (1.2 gm/kg) was administered at 1 hr. After the oral glucose, net splanchnic glucose uptake increased to values 6-fold higher than with intravenous glucose despite unchanged plasma glucose levels and plasma insulin concentrations well below those observed in the studies with euglycemic hyperinsulinemia. The results indicate that hyperinsulinemia or hyperglycemia induced by intravenous infusion of glucose or insulin causes minimal net uptake of glucose by the splanchnic bed despite marked stimulation of total glucose turnover. In contrast, administration of glucose by the oral route has a marked stimulatory effect on net splanchnic glucose uptake. These findings suggest that orally consumed glucose causes the release of a gastrointestinal factor that enhances insulin-mediated glucose uptake by the liver.