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- Title
Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans.
- Authors
Halim, Md Abdul; Degerblad, Marie; Sundbom, Magnus; Karlbom, Urban; Juul Holst, Jens; Webb, Dominic-Luc; Hellström, Per M; Holst, Jens Juul
- Abstract
<bold>Context: </bold>Glucagon-like peptide-1 (GLP-1) secretion from l-cells and postprandial inhibition of gastrointestinal motility.<bold>Objective: </bold>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.<bold>Design: </bold>Single-blind parallel study.<bold>Setting: </bold>University hospital laboratory.<bold>Participants: </bold>Healthy volunteers investigated with antroduodenal manometry. Human gastric and intestinal muscle strips.<bold>Interventions: </bold>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.<bold>Main Outcome Measures: </bold>Postprandial gastrointestinal relaxation by GLP-1.<bold>Results: </bold>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.<bold>Conclusions: </bold>GLP-1 and ROSE-010 inhibit postprandial gastrointestinal motility through GLP-1R at myenteric neurons, involving nitrergic and cyclic adenosine monophosphate-dependent mechanisms.
- Subjects
AUTONOMIC nervous system physiology; AUTONOMIC nervous system; COMPARATIVE studies; DUODENUM; GASTROINTESTINAL motility; MANOMETERS; RESEARCH methodology; MEDICAL cooperation; PEPTIDES; PYLORUS; RESEARCH; GLUCAGON-like peptide 1; EVALUATION research; HUMAN research subjects; BLIND experiment
- Publication
Journal of Clinical Endocrinology & Metabolism, 2017, pN.PAG
- ISSN
0021-972X
- Publication type
journal article
- DOI
10.1210/jc.2017-02006