After a meal, glucagon-like peptide-1 (GLP-1) and glucose levels are significantly greater in the hepatic portal vein than in the artery. We have previously reported that, in the presence of intraportal glucose delivery, a physiological increase of GLP-1 in the hepatic portal vein increases nonhepatic glucose uptake via a mechanism independent of changes in pancreatic hormone secretion. The aim of the present study was to determine whether intraportal glucose delivery is required to observe this effect. Experiments consisted of a 40-min basal period, followed by a 240-min experimental period, during which conscious 42-h fasted dogs received glucose peripherally to maintain arterial plasma glucose levels at approximately 160 mg/dl. In addition, either saline (n = 6) or GLP-1 (1 pmol.kg(-1).min(-1); GLP-1, n = 6) was administered intraportally during the experimental period. As in the previous study, the presence of GLP-1 did not alter pancreatic hormone levels; however, in the present study, intraportal GLP-1 infusion did not result in an increase in whole body glucose utilization. This is despite the fact that arterial and hepatic portal vein GLP-1 levels were maintained at the same level as the previous study. Therefore, a physiological elevation of GLP-1 in the hepatic portal vein does not increase whole body glucose uptake when hyperglycemia is induced by peripheral glucose infusion. This indicates that a physiological increase in GLP-1 augments glucose utilization only when GLP-1 and glucose gradients conditions mimic the postprandial state.