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GLP-1 Inhibits Prandial Antro-Duodeno-Jejunal Motility in Humans: Native GLP-1 Compared With Analogue ROSE-010 In Vitro
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology. 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 Medical Sciences, Gastroenterology/Hepatology. Uppsala University.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery. Uppsala University.
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2016 (English)In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 150, no 4, suppl. 1, S97-S98 p.Article in journal, Meeting abstract (Refereed) Published
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. GLP-1, GLP-2 and 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.

Place, publisher, year, edition, pages
2016. Vol. 150, no 4, suppl. 1, S97-S98 p.
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:uu:diva-303318DOI: 10.1016/S0016-5085(16)30437-1OAI: oai:DiVA.org:uu-303318DiVA: diva2:971442
Conference
Digestive Disease Week 2016, San Diego, USA
Available from: 2016-09-16 Created: 2016-09-16 Last updated: 2016-10-14Bibliographically approved

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Halim, Md. AbdulDominic-Luc, WebbMagnus, SundbomHellström, Per M
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