The aim of this study was to determine whether the elimination of the hepatic arterial-portal (A-P) venous glucose gradient would alter the effects of portal glucose delivery on hepatic or peripheral glucose uptake. Three groups of 42-h-fasted conscious dogs (n = 7/group) were studied. After a 40-min basal period, somatostatin was infused peripherally along with intraportal insulin (7.2 pmol x kg(-1) x min(-1)) and glucagon (0.65 ng x kg(-1) x min(-1)). In test period 1 (90 min), glucose was infused into a peripheral vein to double the hepatic glucose load (HGL) in all groups. In test period 2 (90 min) of the control group (CONT), saline was infused intraportally; in the other two groups, glucose was infused intraportally (22.2 micromol x kg(-1) x min(-1)). In the second group (PD), saline was simultaneously infused into the hepatic artery; in the third group (PD+HAD), glucose was infused into the hepatic artery to eliminate the negative hepatic A-P glucose gradient. HGL was twofold basal in each test period. Net hepatic glucose uptake (NHGU) was 10.1 +/- 2.2 and 12.8 +/- 2.1 vs. 11.5 +/- 1.6 and 23.8 +/- 3.3* vs. 9.0 +/- 2.4 and 13.8 +/- 4.2 micromol x kg(-1) x min(-1) in the two periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). NHGU was 28.9 +/- 1.2 and 39.5 +/- 4.3 vs. 26.3 +/- 3.7 and 24.5 +/- 3.7* vs. 36.1 +/- 3.8 and 53.3 +/- 8.5 micromol x kg(-1) x min(-1) in the first and second periods of CONT, PD, and PD+HAD, respectively (* P < 0.05 vs. same test period in PD and PD+HAD). Thus the increment in NHGU and decrement in extrahepatic glucose uptake caused by the portal signal were significantly reduced by hepatic arterial glucose infusion. These results suggest that the hepatic arterial glucose level plays an important role in generation of the effect of portal glucose delivery on glucose uptake by liver and muscle.