Delivery of glucose into the portal vein is associated with at least a twofold enhancement of net hepatic glucose uptake (NHGU) in comparison with delivery of the same load of glucose via a peripheral vein, even when insulin and glucagon concentrations are kept equivalent with the two routes of delivery. Both the rapidity of the livers response (within 15 minutes after initiating portal glucose infusion) and the fact that the enhancement is nullified by surgical denervation of the liver are consistent with the effect being the result of a neurally mediated signal (referred to as the portal signal). A negative arterial-portal glucose gradient (arterial concentration greater than that in the portal vein) apparently triggers the signal. The location of the arterial glucose sensors that provide the reference information with which to compare the portal vein glucose concentration is as yet unclear, but the central nervous system and the hepatic artery are likely sites. Not only is NHGU enhanced by the portal signal, but also the rate of net hepatic glycogen synthesis is stimulated in the presence of the portal signal. It was recently demonstrated that concomitant intraportal delivery of glucose and a mixture of gluconeogenic ammo acids results in blunting of NHGU Conversely, peripheral infusion of the amino acid mixture did not suppress NHGU. Amino acid sensors in the portal region appear to generate neural signals that modulate glucose uptake by the liver. Moreover, it has been observed that portal glucose delivery, in addition to activating the liver, inhibits glucose uptake by extrahepatic tissues. The portal signal is therefore part of a complex system regulating the partitioning of energy substrates between the liver and the extrahepatic tissues after enteral nutrient intake.