Activation of the hepatoportal glucose sensors by portal glucose infusion leads to increased glucose clearance and induction of hypoglycemia. Here, we investigated whether glucagon-like peptide-1 (GLP-1) could modulate the activity of these sensors. Mice were therefore infused with saline (S-mice) or glucose (P-mice) through the portal vein at a rate of 25 mg/kg · min. In P-mice, glucose clearance increased to 67.5 ± 3.7 mg/kg · min as compared with 24.1 ± 1.5 mg/kg · min in S-mice, and glycemia decreased from 5.0 ± 0.1 to 3.3 ± 0.1 mmol/l at the end of the 3-h infusion period. Coinfusion of GLP-1 with glucose into the portal vein at a rate of 5 pmol/kg · min (P–GLP-1 mice) did not increase the glucose clearance rate (57.4 ± 5.0 ml/kg · min) and hypoglycemia (3.8 ± 0.1 mmol/l) observed in P-mice. In contrast, coinfusion of glucose and the GLP-1 receptor antagonist exendin-(9-39) into the portal vein at a rate of 0.5 pmol/kg · min (P-Ex mice) reduced glucose clearance to 36.1 ± 2.6 ml/kg · min and transiently increased glycemia to 9.2 ± 0.3 mmol/l at 60 min of infusion before it returned to the fasting level (5.6 ± 0.3 mmol/l) at 3 h. When glucose and exendin-(9-39) were infused through the portal and femoral veins, respectively, glucose clearance increased to 70.0 ± 4.6 ml/kg · min and glycemia decreased to 3.1 ± 0.1 mmol/l, indicating that exendin-(9-39) has an effect only when infused into the portal vein. Finally, portal vein infusion of glucose in GLP-1 receptor^−/− mice failed to increase the glucose clearance rate (26.7 ± 2.9 ml/kg · min). Glycemia increased to 8.5 ± 0.5 mmol/l at 60 min and remained elevated until the end of the glucose infusion (8.2 ± 0.4 mmol/l). Together, our data show that the GLP-1 receptor is part of the hepatoportal glucose sensor and that basal fasting levels of GLP-1 sufficiently activate the receptor to confer maximum glucose competence to the sensor. These data demonstrate an important extrapancreatic effect of GLP-1 in the control of glucose homeostasis.