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Submitted on February 10, 2006
Accepted on June 13, 2007
Department of Medicine, University of Cincinnati, Cincinnati, OH; Department of Psychiatry, University of Cincinnati, Cincinnati, OH
* To whom correspondence should be addressed. E-mail: dalessd{at}ucmail.uc.edu.
Glucagon-like peptide-1 (GLP-1) is an intestinal hormone that is secreted during meal absorption and it 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-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 intra-portal infusion of the GLP-1r antagonist, [des-His1, Glu9]-Exendin-4, in a low dose, had glucose intolerance, with a 53% higher glucose excursion compared to a vehicle-infused control group. Infusion of [des-His1, Glu9]-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-1 receptors are present on nerve terminals in the hepatic portal bed and 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.
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