Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats.
Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that is secreted during meal absorption and is essential for normal glucose homeostasis. However, the relatively low plasma levels and rapid metabolism of GLP-1 raise questions as to whether direct endocrine action on target organs, such as islet cells, account for all of its effects on glucose tolerance. Recently, an alternative neural pathway initiated by sensors in the hepatic portal region has been proposed to mediate GLP-1 activity. We hypothesized that visceral afferent neurons in the portal bed express the GLP-1 receptor (GLP-1r) and regulate glucose tolerance. Consistent with this hypothesis, GLP-1r mRNA was present in the nodose ganglia, and nerve terminals innervating the portal vein contained the GLP-1r. Rats given an intraportal infusion of the GLP-1r antagonist, [des-His(1),Glu(9)] exendin-4, in a low dose, had glucose intolerance, with a 53% higher glucose excursion compared with a vehicle-infused control group. Infusion of [des-His(1),Glu(9)] exendin-4 at an identical rate into the jugular vein had no effect on glucose tolerance, demonstrating that this dose of GLP-1r antagonist did not affect blood glucose due to spillover into the systemic circulation. These studies demonstrate that GLP-1r are present on nerve terminals in the hepatic portal bed and that GLP-1 antagonism localized to this region impairs glucose tolerance. These data are consistent with an important component of neural mediation of GLP-1 action.
Vahl
Torsten P
TP
Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, Ohio 45267, USA.
Tauchi
Miyuki
M
Durler
Timothy S
TS
Elfers
Eileen E
EE
Fernandes
Timothy M
TM
Bitner
Ronald D
RD
Ellis
Kay S
KS
Woods
Stephen C
SC
Seeley
Randy J
RJ
Herman
James P
JP
D'Alessio
David A
DA
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000502:physiology*; D018149:Glucose Intolerance / Q000139:chemically induced; D005951:Glucose Tolerance Test; D007262:Infusions, Intravenous; D008099:Liver / Q000098:blood supply; D008297:Male; D009411:Nerve Endings / Q000378:metabolism*; D009620:Nodose Ganglion / Q000378:metabolism; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects / Q000294:innervation* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology
D001786:Blood Glucose; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D005947:Glucose