GLP-1 Inhibits Prandial Antro-duodeno-jejunal Motility in Humans

Overview

The inhibitory effect of low dose GLP-1 is investigated on prandial motility of the stomach, duodenum and jejunum in vivo in humans. Supplementary in vitro studies on the mechanism of action of the GLP-1 inhibition of motility as carried out on muscle strips from the upper gastrointestinal tract in man.

Full Title of Study: “GLP-1 Inhibits Prandial Antro-duodeno-jejunal Motility in Humans: Native GLP-1 Compared With Analogue ROSE-010 in Vitro”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Basic Science
    • Masking: Single (Participant)
  • Study Primary Completion Date: August 2017

Detailed Description

Twelve healthy volunteers will undergo antroduodenojejunal manometry. Baseline recording with infusion of saline for 1 hour is compared with infusion of GLP-1 0.7 and 1.2 pmol per kg minute for another 1 hour. Plasma GLP-1 and GLP-2 is measured by RIA. Responses to GLP-1 will be measured after food intake as prandial response to GLP-1. The outcome will be evaluated as change in motility index from baseline to meal-stimulated conditions and during influence of GLP-1. Further in vitro studies of gastrointestinal muscle strips, precontracted with bethanechol or electric field stimulation, are planned to investigate the response to GLP-1 or GLP-1 analogue ROSE-010. GLP-1 and GLP-2 receptor immunoreactivity is localized by immunohistochemistry. Receptor mediated mechanisms are studied with GLP-1 receptor blocker exendin(9-39)amide, nitro-monomethyl arginine to block nitric oxide synthase and tetrodotoxin to block sodium channels and nerve conduction.

Interventions

  • Biological: GLP-1
    • Intravenous infusion of GLP-1
  • Biological: Intravenous saline
    • Control

Arms, Groups and Cohorts

  • Experimental: GLP-1
    • Intravenous infusion of GLP-1 at 0.7 and 1.2 mol/kg per minute
  • Placebo Comparator: Control
    • Intravenous saline

Clinical Trial Outcome Measures

Primary Measures

  • Motility index (measure of contraction amplitude x duration; area for mmHg x sec)
    • Time Frame: 60 minutes
    • Inhibition of prandially increased motility index (motor activity in the antrum and upper small intestine).

Secondary Measures

  • Smooth muscle relaxation induced by GLP-1
    • Time Frame: 6 hours
    • Separate experiments in vitro: GLP-1-induced inhibition of bethanechol-stimulated smooth muscle strips to characterize GLP-1′s pharmacological action.
  • Presence of GLP-1 and GLP-2 receptors in gastric and small bowel tissue
    • Time Frame: 1 day
    • Separate experiments in vitro: Antibody staining of gastric and small bowel tissue for receptors of GLP-1 and GLP-2

Participating in This Clinical Trial

Inclusion Criteria

  • Healthy volunteers over 18 years of age. Exclusion Criteria:
  • Any medical condition. – Any drug treatment.
  • Gender Eligibility: All

    Minimum Age: 18 Years

    Maximum Age: 60 Years

    Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

    Investigator Details

    • Lead Sponsor
      • Uppsala University
    • Collaborator
      • Karolinska Institutet
    • Provider of Information About this Clinical Study
      • Principal Investigator: Per Hellström, Professor – Uppsala University
    • Overall Official(s)
      • Per M. Hellström, MD, PhD, Principal Investigator, Uppsala University

    References

    Edholm T, Degerblad M, Grybäck P, Hilsted L, Holst JJ, Jacobsson H, Efendic S, Schmidt PT, Hellström PM. Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis. Neurogastroenterol Motil. 2010 Nov;22(11):1191-200, e315. doi: 10.1111/j.1365-2982.2010.01554.x.

    Hellström PM, Hein J, Bytzer P, Björnssön E, Kristensen J, Schambye H. Clinical trial: the glucagon-like peptide-1 analogue ROSE-010 for management of acute pain in patients with irritable bowel syndrome: a randomized, placebo-controlled, double-blind study. Aliment Pharmacol Ther. 2009 Jan;29(2):198-206. doi: 10.1111/j.1365-2036.2008.03870.x. Epub 2008 Oct 10.

    Citations Reporting on Results

    Hellström PM, Näslund E, Edholm T, Schmidt PT, Kristensen J, Theodorsson E, Holst JJ, Efendic S. GLP-1 suppresses gastrointestinal motility and inhibits the migrating motor complex in healthy subjects and patients with irritable bowel syndrome. Neurogastroenterol Motil. 2008 Jun;20(6):649-59. doi: 10.1111/j.1365-2982.2007.01079.x. Epub 2008 Feb 19.

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