Glucagon-Like Peptide-1 Inhibits Prandial Gastrointestinal Motility Through Myenteric Neuronal Mechanisms in Humans

J Clin Endocrinol Metab. 2018 Feb 1;103(2):575-585. doi: 10.1210/jc.2017-02006.

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.

Trial registration: ClinicalTrials.gov NCT02731664.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Duodenum / drug effects
  • Gastric Emptying / drug effects
  • Gastrointestinal Motility / drug effects*
  • Glucagon-Like Peptide 1 / analogs & derivatives
  • Glucagon-Like Peptide 1 / pharmacology*
  • Healthy Volunteers
  • Humans
  • Male
  • Manometry
  • Middle Aged
  • Myenteric Plexus / drug effects*
  • Myenteric Plexus / physiology
  • Peptide Fragments / pharmacology
  • Pyloric Antrum / drug effects
  • Single-Blind Method
  • Young Adult

Substances

  • Peptide Fragments
  • glucagon-like peptide (7-37), valyl(10)-
  • Glucagon-Like Peptide 1

Associated data

  • ClinicalTrials.gov/NCT02731664