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Endocrinology ; 148(10): 4965-73, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17584962

RESUMO

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.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/fisiologia , Glucose/fisiologia , Terminações Nervosas/metabolismo , Veia Porta/inervação , Receptores de Glucagon/fisiologia , Animais , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Linhagem Celular , Relação Dose-Resposta a Droga , Exenatida , Receptor do Peptídeo Semelhante ao Glucagon 1 , Intolerância à Glucose/induzido quimicamente , Teste de Tolerância a Glucose , Infusões Intravenosas , Fígado/irrigação sanguínea , Masculino , Gânglio Nodoso/metabolismo , Peptídeos/administração & dosagem , Peptídeos/farmacologia , Veia Porta/efeitos dos fármacos , Veia Porta/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Glucagon/antagonistas & inibidores , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Peçonhas/administração & dosagem , Peçonhas/farmacologia
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