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GLP-1 acts at myenteric neurons to inhibit motility in humans: results of in vivo motility studies and in vitro characterization of responses to GLP-1 and ROSE-010: GLP-1 and digestive motility
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University. (Gastroenterology & Hepatology)ORCID iD: 0000-0001-6220-3936
Karolinska Institutet. (Growth and Metabolism)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Uppsala University.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University. (Gastroenterology & Hepatology)
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Glucagon-like peptide-1 (GLP-1) is secreted from L-cells after nutrient ingestion, inhibiting motility. Aims: To clarify whether infused GLP-1 inhibits in vivo prandial motility response and determine the likeliest target cell type and mechanism of action of GLP-1 and its analogue ROSE-010 using in vitro human gut muscle strips. Methods: Sixteen healthy volunteers underwent antroduodenojejunal manometry. Recordings of 1 hour infusion of saline or GLP-1 (0.7 or 1.2 pmol/kg/min) were compared. Plasma GLP-1 and GLP-2 were measured by RIA. Gastrointestinal muscle strips from surgical re-sections, pre-contracted with bethanechol or electric field stimulation (EFS), were investigated for GLP-1 or ROSE-010 induced relaxation. Receptors for GLP-1 and GLP-2 (GLP-1R, GLP-2R) were visualized by immunohistochemistry. Mechanisms were studied employing exendin(9-39) amide, Lw-nitro-monomethyl arginine (L-NMMA), 2´5´-dideoxyadenosine (DDA) and tetrodotoxin (TTX). Results: Food-intake increased motility index from 4.0±0.5 to 6.4±0.3 (antrum), 4.2±0.4 to 5.7±0.4 (duodenum) and 4.6±0.3 to 5.9±0.2 (jejunum) ln(Σ(mmHg·s·min-1)). GLP-1 at 0.7 pmol/kg/minwas sufficient to suppress these indexes from 6.2±0.4 to 3.8±0.7, 5.6±0.6 to 3.9±0.6 and 5.8±0.1 to 4.6±0.4 ln(Σ(mmHg·s·min-1)). Both GLP-1 doses raised plasma GLP-1, but not GLP-2. GLP-1 (EC50 40 nM) and ROSE-010 (EC50 50 nM) relaxed bethanechol-induced contractions in muscle strips. Inhibitory responses were blocked by exendin(9-39) amide, L-NMMA, DDA or TTX pre-treatment. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle. Conclusions: GLP-1 and ROSE-010 inhibit motility through GLP-1R at myenteric neurons, which also possess GLP-2 receptors. GLP-1 increases more than GLP-2 with meals and does not increase plasma GLP-2. GLP-1 and ROSE-010 relaxations are cAMP and NO dependent.

Keyword [en]
Antroduodenojejunal motility, Glucagon-like peptides, Peptide hormones, ROSE-010, exendin(9-39) amide
National Category
Medical and Health Sciences
Research subject
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-294388OAI: oai:DiVA.org:uu-294388DiVA: diva2:929733
Available from: 2016-05-19 Created: 2016-05-19 Last updated: 2016-05-25
In thesis
1. Gut peptides in gastrointestinal motility and mucosal permeability
Open this publication in new window or tab >>Gut peptides in gastrointestinal motility and mucosal permeability
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Gut regulatory peptides, such as neuropeptides and incretins, play important roles in hunger, satiety and gastrointestinal motility, and possibly mucosal permeability. Many peptides secreted by myenteric nerves that regulate motor control are also produced in mucosal epithelial cells. Derangements in motility and mucosal permeability occur in many diseases. Current knowledge is fragmentary regarding gut peptide actions and mechanisms in motility and permeability.

This thesis aimed to 1) develop probes and methods for gut permeability testing, 2) elucidate the role of neuropeptide S (NPS) in motility and permeability, 3) characterize nitrergic muscle relaxation and 4) characterize mechanisms of glucagon-like peptide 1 (GLP-1) and the drug ROSE-010 (GLP-1 analog) in motility inhibition.

A rapid fluorescent permeability test was developed using riboflavin as a transcellular transport probe and the bisboronic acid 4,4'oBBV coupled to the fluorophore HPTS as a sensor for lactulose, a paracellular permeability probe. This yielded a lactulose:riboflavin ratio test.

NPS induced muscle relaxation and increased permeability through NO-dependent mechanisms. Organ bath studies revealed that NPS induced NO-dependent muscle relaxation that was tetrodotoxin (TTX) sensitive. In addition to the epithelium, NPS and its receptor NPSR1 localized at myenteric nerves. Circulating NPS was too low to activate NPSR1, indicating NPS uses local autocrine/paracrine mechanisms.

Nitrergic signaling inhibition by nitric oxide synthase inhibitor L-NMMA elicited premature duodenojejunal phase III contractions in migrating motility complex (MMC) in humans. L-NMMA shortened MMC cycle length, suppressed phase I and shifted motility towards phase II. Pre-treatment with atropine extended phase II, while ondansetron had no effect. Intestinal contractions were stimulated by L-NMMA, but not TTX. NOS immunoreactivity was detected in the myenteric plexus but not smooth muscle.

Food-intake increased motility of human antrum, duodenum and jejunum. GLP-1 and ROSE-010 relaxed bethanechol-induced contractions in muscle strips. Relaxation was blocked by GLP-1 receptor antagonist exendin(9-39) amide, L-NMMA, adenylate cyclase inhibitor 2´5´-dideoxyadenosine or TTX. GLP-1R and GLP-2R were expressed in myenteric neurons, but not muscle.

In conclusion, rapid chemistries for permeability were developed while physiological mechanisms of NPS, nitrergic and GLP-1 and ROSE-010 signaling were revealed. In the case of NPS, a tight synchrony between motility and permeability was found.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 58 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1233
Keyword
Gut regulatory peptides, Neuropeptides, Gastrointestinal mucosal permeability, Gastrointestinal motility, GLP-1, NPS, ROSE-010
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-294390 (URN)978-91-554-9607-4 (ISBN)
Public defence
2016-06-14, Enghoffsalen, Entrance 50, Uppsala University Hospital, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2016-05-24 Created: 2016-05-19 Last updated: 2016-06-15

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Halim, Md Abdul
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