Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor.
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.
Burcelin
R
R
Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland.
Da Costa
A
A
Drucker
D
D
Thorens
B
B
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002408:Catheters, Indwelling; D004797:Enzyme-Linked Immunosorbent Assay; D005215:Fasting; D005268:Femoral Vein; D005768:Gastrointestinal Hormones / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000008:administration & dosage; D006503:Hepatic Veins / Q000502:physiology; D006706:Homeostasis; D007262:Infusions, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000494:pharmacology*; D011168:Portal System / Q000502:physiology*; D011169:Portal Vein / Q000502:physiology; D011498:Protein Precursors / Q000494:pharmacology*; D014316:Tritium; D014688:Venoms / Q000494:pharmacology
D001786:Blood Glucose; D005768:Gastrointestinal Hormones; D010446:Peptide Fragments; D011498:Protein Precursors; D014688:Venoms; D014316:Tritium; C055453:glucagon-like peptide 1 (7-36)amide; C083773:exendin (9-39); D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose