Md Abdul Halim1, Marie Degerblad2, Magnus Sundbom3, Urban Karlbom3, Jens Juul Holst4, Dominic-Luc Webb1, Per M Hellström1. 1. Department of Medical Sciences, Gastroenterology Unit, Uppsala University, Uppsala, Sweden. 2. Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden. 3. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. 4. NNF Center for Basic Metabolic Research and Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Abstract
Context: Glucagon-like peptide-1 (GLP-1) secretion from l-cells and postprandial inhibition of gastrointestinal motility. Objective: Investigate whether physiological plasma concentrations of GLP-1 inhibit human postprandial motility and determine mechanism of action of GLP-1 and analog ROSE-010 action. Design: Single-blind parallel study. Setting: University hospital laboratory. Participants: Healthy volunteers investigated with antroduodenal manometry. Human gastric and intestinal muscle strips. Interventions: Motility indices (MIs) obtained before and during GLP-1 or saline infusion. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips investigated for GLP-1- and ROSE-010-induced relaxation employing GLP-1 and GLP-2 and their receptor localization, and blockers exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2',5'-dideoxyadenosine (DDA), and tetrodotoxin (TTX) to reveal target mechanism of GLP-1 action. Main Outcome Measures: Postprandial gastrointestinal relaxation by GLP-1. Results: In humans, food intake increased MI to 6.4 ± 0.3 (antrum), 5.7 ± 0.4 (duodenum), and 5.9 ± 0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg/min suppressed corresponding MI to 4.6 ± 0.2, 4.7 ± 0.4, and 5.0 ± 0.2, whereas 1.2 pmol/kg/min suppressed MI to 5.4 ± 0.2, 4.4 ± 0.3, and 5.4 ± 0.3 (P < 0.0001 to 0.005). In vitro, GLP-1 and ROSE-010 prevented contractions by bethanechol and electric field stimulation (P < 0.005 to 0.05). These effects were disinhibited by exendin(9-39)amide, L-NMMA, DDA, or TTX. GLP-1 and GLP-2 were localized to epithelial cells, GLP-1 also at myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle. Conclusions: GLP-1 and ROSE-010 inhibit postprandial gastrointestinal motility through GLP-1R at myenteric neurons, involving nitrergic and cyclic adenosine monophosphate-dependent mechanisms.
Context:Glucagon-like peptide-1 (GLP-1) secretion from l-cells and postprandial inhibition of gastrointestinal motility. Objective: Investigate whether physiological plasma concentrations of GLP-1 inhibit human postprandial motility and determine mechanism of action of GLP-1 and analog ROSE-010 action. Design: Single-blind parallel study. Setting: University hospital laboratory. Participants: Healthy volunteers investigated with antroduodenal manometry. Human gastric and intestinal muscle strips. Interventions: Motility indices (MIs) obtained before and during GLP-1 or saline infusion. Plasma GLP-1 and glucagon-like peptide-2 (GLP-2) measured by radioimmunoassay. Gastrointestinal muscle strips investigated for GLP-1- and ROSE-010-induced relaxation employing GLP-1 and GLP-2 and their receptor localization, and blockers exendin(9-39)amide, Lω-nitro-monomethylarginine (L-NMMA), 2',5'-dideoxyadenosine (DDA), and tetrodotoxin (TTX) to reveal target mechanism of GLP-1 action. Main Outcome Measures: Postprandial gastrointestinal relaxation by GLP-1. Results: In humans, food intake increased MI to 6.4 ± 0.3 (antrum), 5.7 ± 0.4 (duodenum), and 5.9 ± 0.2 (jejunum). GLP-1 administered intravenously raised plasma GLP-1, but not GLP-2. GLP-1 0.7 pmol/kg/min suppressed corresponding MI to 4.6 ± 0.2, 4.7 ± 0.4, and 5.0 ± 0.2, whereas 1.2 pmol/kg/min suppressed MI to 5.4 ± 0.2, 4.4 ± 0.3, and 5.4 ± 0.3 (P < 0.0001 to 0.005). In vitro, GLP-1 and ROSE-010 prevented contractions by bethanechol and electric field stimulation (P < 0.005 to 0.05). These effects were disinhibited by exendin(9-39)amide, L-NMMA, DDA, or TTX. GLP-1 and GLP-2 were localized to epithelial cells, GLP-1 also at myenteric neurons. GLP-1R and GLP-2R were localized at myenteric neurons but not muscle. Conclusions: GLP-1 and ROSE-010 inhibit postprandial gastrointestinal motility through GLP-1R at myenteric neurons, involving nitrergic and cyclic adenosine monophosphate-dependent mechanisms.
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