Portal glucose delivery enhances net hepatic glucose uptake (NHGU) relative to peripheral glucose delivery. The "portal signal" appears to be neurally mediated, but the mechanisms involved are unclear. We hypothesize that the sympathetic nervous system normally restrains NHGU, and that portal glucose delivery relieves the inhibition. Studies were performed on two groups of 42-h-fasted conscious dogs that underwent laparotomy for vascular cannulation ~16 days before study. The DEN group (n=10) underwent selective sympathetic denervation by cutting the nerves at the celiac nerve bundle near the common hepatic artery; the CON group (n=10) underwent a sham procedure. After a basal period (-140 to 0 min), somatostatin (0.8 µg/kg/min) was given along with basal intraportal infusions of insulin and glucagon. Glucose was infused peripherally to double the glucose level during a 90 min period (P1). In P2, glucose was infused intraportally (3-4 mg/kg/min) and the peripheral glucose infusion was reduced to maintain the hepatic glucose load (HGL) for 90 minutes. This was then followed by a 3^rd 90 minute period (P3) in which the portal glucose infusion was terminated and peripheral glucose infusion was increased to maintain the HGL. The average HGLs (mg/kg/min) in the CON and DEN groups were 53±3 and 54±4 in P1, 55±3 and 55±4 in P2, and 57±3and 55±5 in P3, respectively. The arterial insulin levels remained basal in both groups, as did the glucagon levels. NHGU (mg/kg/min) in the CON group averaged 1.7±0.3 during peripheral glucose infusion and increased to 2.9±0.3 during portal glucose infusion (P2). NHGU (mg/kg/min) was significantly greater in DEN than CON (P<0.05) during peripheral glucose infusion (2.9±0.4) and failed to increase significantly (3.2±0.2) during portal glucose infusion (P2) (NS relative to CON). Selective sympathetic denervation resulted in an increase in NHGU in response to hyperglycemia but a significantly blunted the response to portal glucose delivery.