Effects of Exendin(9-39) on Gastroduodenal Motility

March 31, 2015 updated by: Ludwig-Maximilians - University of Munich

Regulation of Antro-pyloro-duodenal and Proximal Gastric Motility by GLP-1: Involvement of Cholinergic Pathways

The purpose of this study in humans is to define the effects of the endogenous hormone GLP-1 on gastroduodenal motility and on endocrine pancreatic secretion by using the specific GLP-1 receptor antagonist exendin(9-39). To elucidate possible cholinergic pathways, we combined exendin(9-39) with the muscarinergic antagonist atropine.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Following a meal, gut-produced incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the circulation. GLP-1 and GIP, the two dominant incretin hormones, are part of a natural endogenous system involved in maintaining glucose homeostasis. In the presence of normal or elevated, but not low, glucose concentration, both GLP-1 and GIP increase insulin secretion from pancreatic islet beta-cells. GLP-1 also lowers glucagon secretion from pancreatic alpha-cells and delays nutrient delivery from the stomach by inhibiting gastric emptying. These combined effects improve glucose tolerance providing the rationale for a therapeutic potential of GLP-1 analogues in the treatment of diabetes mellitus.

A dominant gastrointestinal action of synthetic GLP-1 is the inhibition of gastroduodenal and stimulation of pyloric motility, resulting in a delay of gastric emptying and in decreased glycemic excursions. Postprandial glucose fluctuations have been demonstrated to be an important determinant of glycemic control as assessed by A1C. Moreover, emerging evidence shows a strong link between transient postprandial hyperglycemia and microvascular and macrovascular complications in diabetes mellitus. Deceleration of gastric emptying is now considered as mechanism to lower postprandial glycemia in patients with diabetes mellitus. It is part of the pharmacodynamic profile of new antidiabetic incretinomimetica. In contrast, inhibition of the enzyme dipeptidylpeptidase 4 (DPP-4) which is responsible for the rapid degradation of GLP-1 failed to show an effect on gastric emptying in human although plasma GLP-1 was increased by twofold. Most of our understanding of the effects of GLP-1 is based upon studies employing synthetic GLP-1 whereas only little is known about endogenously released GLP-1.

Using the specific GLP-1 receptor antagonist exendin(9-39) we were able to show that endogenous GLP-1 acts as an incretin hormone in human. Moreover, the inhibition of antroduodenal and the stimulation of pyloric motility during a duodenal glucose load were reversed by the GLP-1 receptor antagonist. In order to more completely evaluate the effects of GLP-1 as an enterogastrone, the present study examines the effects of exendin(9-39) on antropyloroduodenal and proximal gastric motility during a physiological meal. As cholinergic pathways are thought to be involved in inhibitory actions of GLP-1 we combine the GLP-1 receptor antagonist with the muscarinergic antagonist atropine. To ensure a comparable stimulation of GLP-1 under all experimental conditions we decide to perfuse the meal directly into the duodenum.

Comparisons: In ten healthy volunteers, an interdigestive period is followed by 70 min with duodenal perfusion of a mixed liquid meal (250 kcal). On four days and in random order, exendin(9-39) (300 pmol•kg-1•min-1), atropine (5 µg•kg-1•h-1), exendin(9-39) + atropine or saline are intravenously infused. Antro-pyloro-duodenal perfusion manometry and fundic motility (electronic barostat) are assessed in parallel. Isobaric distensions of the proximal stomach were performed determining compliance.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Munich, Germany, 81377
        • Clinical Research unit, Dept. of Internal Medicine II - Großhadern, University of Munich

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male or female (postmenopausal, surgically sterile or using double-barrier method of contraception) healthy volunteers
  • Age 18-65 years
  • Body mass index (BMI) < 30 kg/m2
  • Must have a fasting blood glucose below 100 mg/dl at screening and on all study days
  • Able to provide written informed consent prior to study participation
  • Able to communicate well with the investigator and comply with the requirements of the study

Exclusion Criteria:

  • Diabetes mellitus
  • Treatment with systemic steroids and thyroid hormone
  • Patients with any history of gastrointestinal surgery, e.g. partial bowel resections, partial gastric resections, etc.
  • Participation in any clinical investigation within 4 weeks prior to dosing or longer if required by local regulation.
  • Donation or loss of 400 mL or more of blood within 8 weeks prior to dosing.
  • Significant illness within the two weeks prior to dosing.
  • Past medical history of clinically significant electrocardiogram (ECG) abnormalities or a family history of a prolonged QT-interval syndrome.
  • History of clinically significant drug allergy; history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug.
  • Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the subject in case of participation in the study. The investigator should be guided by evidence of any of the following:
  • history of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding
  • history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection
  • history or clinical evidence of pancreatic injury or pancreatitis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: saline-saline

saline IV

+ saline IV
Active Comparator: saline-exendin(9-39)amide

saline IV

+ exendin(9-39)amide IV
Drug: exendin(9-39)amide
Active Comparator: saline-atropine

saline IV

+ atropine IV
Drug: atropine
Active Comparator: exendin(9-39)amide-atropine

exendin(9-39)amide IV

+ atropine IV
Drug: exendin(9-39)amide
Drug: atropine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Effect of exendin(9-39) on gastroduodenal motility Effect of exendin(9-39) on gastroduodenal motility with simultaneous atropine
Time Frame: within the 200 min study period
within the 200 min study period

Secondary Outcome Measures

Outcome Measure
Time Frame
Effect of exendin(9-39) on blood glucose levels and plasma immunoreactivities of insulin, glucagon, and pancreatic polypeptide
Time Frame: within the 200 min study period
within the 200 min study period

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ludwig-Maximilians - University of Munich

Collaborators

German Research Foundation
Philipps University Marburg Medical Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 1999

Primary Completion

December 7, 2022

Study Completion (Actual)

September 1, 2000

Study Registration Dates

First Submitted

April 30, 2007

First Submitted That Met QC Criteria

April 30, 2007

First Posted (Estimate)

May 1, 2007

Study Record Updates

Last Update Posted (Estimate)

April 1, 2015

Last Update Submitted That Met QC Criteria

March 31, 2015

Last Verified

April 1, 2007

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • MATEX
  • DFG Ar149/1-2
  • DFG 527/5-2

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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