GLP-1 Inhibits Prandial Antro-Duodeno-Jejunal Motility in Humans: Native GLP-1 Compared With Analogue ROSE-010 In Vitro

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Halim, Md. Abdul,1983-Uppsala universitet,Gastroenterologi/hepatologi,Uppsala University,Gastroenterology & Hepatology (author)

GLP-1 Inhibits Prandial Antro-Duodeno-Jejunal Motility in Humans: Native GLP-1 Compared With Analogue ROSE-010 In Vitro

Article/chapterEnglish2016

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2016
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LIBRIS-ID:oai:DiVA.org:uu-303318
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-303318URI
https://doi.org/10.1016/S0016-5085(16)30437-1DOI
http://kipublications.ki.se/Default.aspx?queryparsed=id:135204295URI

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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.

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Marie, DegerbladKarolinska Institutet (author)
Dominic-Luc, WebbUppsala universitet,Gastroenterologi/hepatologi,Uppsala University(Swepub:uu)domwe127 (author)
Magnus, SundbomUppsala universitet,Gastrointestinalkirurgi,Uppsala University(Swepub:uu)magsundb (author)
Hellström, Per MUppsala universitet,Gastroenterologi/hepatologi,Uppsala University(Swepub:uu)perhe742 (author)
Uppsala universitetGastroenterologi/hepatologi (creator_code:org_t)

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In:Gastroenterology150:4, suppl. 1, s. S97-S980016-50851528-0012

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By the author/editor: Halim, Md. Abdul ...; Marie, Degerblad; Dominic-Luc, Web ...; Magnus, Sundbom; Hellström, Per M

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Gastroenterology ...

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By the university: Uppsala University; Karolinska Institutet

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