title: The insulinotropic effect of exogenous glucagon-like peptide-1 is not affected by acute vagotomy in anaesthetized pigs.
abstract: What is the central question of this study? We investigated whether intestinal vagal afferents are necessary for the insulinotropic effect of glucagon-like peptide-1 (GLP-1) infused into a mesenteric artery or a peripheral vein before and after acute truncal vagotomy. What is the main finding and its importance? We found no effect of truncal vagotomy on the insulinotropic effect of exogenous GLP-1 and speculate that high circulating concentrations of GLP-1 after i.v. and i.a. infusion might have overshadowed any neural signalling component. We propose that further investigations into the possible vagal afferent signalling of GLP-1 would best be pursued using enteral stimuli to provide high subepithelial levels of endogenous GLP-1. Glucagon-like peptide 1 (GLP-1) is secreted from the gut in response to luminal stimuli and stimulates insulin secretion in a glucose-dependent manner. As a result of rapid enzymatic degradation of GLP-1 by dipeptidyl peptidase-4, a signalling pathway involving activation of intestinal vagal afferents has been proposed. We conducted two series of experiments in α-chloralose-anaesthetized pigs. In protocol I, pigs (n = 14) were allocated for either i.v. or i.a. (mesenteric) GLP-1 infusions (1 and 2 pmol kg(-1)  min(-1) , 30 min) while maintaining permissive glucose concentrations at 6 mmol l(-1) by i.v. glucose infusion. The GLP-1 infusions were repeated after acute truncal vagotomy. In protocol II, pigs (n = 27) were allocated into six groups. Glucagon-like peptide 1 was infused i.v. or i.a. (mesenteric) for 1 h at 3 or 30 pmol kg(-1)  min(-1) . During the steady state (21 min into the GLP-1 infusion), glucose (0.2 g kg(-1) , i.v.) was administered over 9 min to stimulate β-cell secretion. Thirty minutes after the glucose infusion, GLP-1 infusions were discontinued. Following a washout period, the vagal trunks were severed in four of six groups (vagal trunks were left intact in two of six groups), whereupon all infusions were repeated. We found no effect of vagotomy on insulin or glucagon secretion during administration of exogenous GLP-1 in any experiment. We speculate that the effect of exogenous GLP-1 overshadowed any effect occurring via the vagus. Within dosage groups, total GLP-1 concentrations were similar, but intact GLP-1 concentrations were much lower when infused via the mesenteric artery because of extensive degradation of GLP-1 in the splanchnic bed. This demonstrates the effectiveness with which intestinal capillary dipeptidyl peptidase-4 protects the systemic circulation from intact GLP-1, consistent with a local role for GLP-1 involving activation of vagal pathways.
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Simon
authors.initials: S
authors.lastname: Veedfald
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Marie
authors.initials: M
authors.lastname: Hansen
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Louise Wulff
authors.initials: LW
authors.lastname: Christensen
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Sara Agnete Hjort
authors.initials: SA
authors.lastname: Larsen
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Karina Rahr
authors.initials: KR
authors.lastname: Hjøllund
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Astrid
authors.initials: A
authors.lastname: Plamboeck
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bolette
authors.initials: B
authors.lastname: Hartmann
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Carolyn Fiona
authors.initials: CF
authors.lastname: Deacon
authors.affiliation: Department of Biomedical Sciences (endocrinology section) and NNF Center for Basic Metabolic Research (translational metabolic physiology section), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens Juul
authors.initials: JJ
authors.lastname: Holst
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D013552:Swine; D014628:Vagotomy / Q000379:methods; D014630:Vagus Nerve / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D005947:Glucose