The aim of this study was to assess the decay of the effect of the portal signal on net hepatic glucose uptake (NHGU). Experiments were performed on five 42-h-fasted conscious dogs. After the 40-min basal period, somatostatin was given peripherally along with insulin (1.8 pmol. kg-1. min-1) and glucagon (0.65 ng. kg-1. min-1) intraportally. In the first experimental period (Pe-GLU-1; 90 min), glucose was infused into a peripheral vein to double the glucose load to the liver (HGL). In the second experimental period (Po-GLU; 90 min), glucose (20.1 micromol. kg-1. min-1) was infused intraportally and the peripheral glucose infusion was reduced to maintain the same HGL. In the third period (Pe-GLU-2; 120 min), the portal glucose infusion was stopped and the peripheral glucose infusion was increased to again sustain HGL. Arterial insulin levels (42 +/- 3, 47 +/- 3, 43 +/- 3 pmol/l) were basal and similar in the Pe-GLU-1, Po-GLU, and Pe-GLU-2 periods, respectively. Arterial glucagon levels were also basal and similar (51 +/- 3, 49 +/- 2, 46 +/- 2 ng/l) in the three experimental periods. The glucose loads to the liver were 251 +/- 11, 274 +/- 14, and 276 +/- 12 micromol. kg-1. min-1, respectively. NHGU was 6.3 +/- 2.4, 19.1 +/- 2.8, and 9.2 +/- 1.2 micromol. kg-1. min-1, and nonhepatic glucose uptake (non-HGU) was 23.6 +/- 3.0, 5.3 +/- 1.8, and 25.5 +/- 3.7 micromol. kg-1. min-1 in the three periods, respectively. Cessation of the portal signal for only 10 min shifted NHGU and non-HGU to 9.4 +/- 2.2 and 25.0 +/- 2.8 micromol. kg-1. min-1, respectively; thus the effect of the portal signal was rapidly reversed both at the liver and peripheral tissues.