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Glucose Competence of the Hepatoportal Vein Sensor Requires the Presence of an Activated Glucagon-Like Peptide-1 Receptor

¹ Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland
² University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada

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.

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