Effects of Exendin(9-39) on Gastroduodenal Motility
Information source: Ludwig-Maximilians - University of Munich
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Digestive Physiology; Gastrointestinal Motility; Gastrointestinal Hormones; Glucagon-like Peptide 1; Exendin (9-39)
Intervention: exendin(9-39)amide (Drug); atropine (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: Ludwig-Maximilians - University of Munich Official(s) and/or principal investigator(s): Joerg Schirra, MD, Principal Investigator, Affiliation: Clinical Research Unit, Dept. of Internal Medicine II, University of Munich
Summary
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.
Clinical Details
Official title: Regulation of Antro-pyloro-duodenal and Proximal Gastric Motility by GLP-1: Involvement of Cholinergic Pathways
Study design: Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double-Blind, Primary Purpose: Diagnostic
Primary outcome: Effect of exendin(9-39) on gastroduodenal motility Effect of exendin(9-39) on gastroduodenal motility with simultaneous atropine
Secondary outcome: Effect of exendin(9-39) on blood glucose levels and plasma immunoreactivities of insulin, glucagon, and pancreatic polypeptide
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 65 Years.
Gender(s): Both.
Criteria:
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
Locations and Contacts
Clinical Research unit, Dept. of Internal Medicine II - Großhadern, University of Munich, Munich 81377, Germany
Additional Information
Related publications: Schirra J, Sturm K, Leicht P, Arnold R, Göke B, Katschinski M. Exendin(9-39)amide is an antagonist of glucagon-like peptide-1(7-36)amide in humans. J Clin Invest. 1998 Apr 1;101(7):1421-30. Schirra J, Houck P, Wank U, Arnold R, Göke B, Katschinski M. Effects of glucagon-like peptide-1(7-36)amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans. Gut. 2000 May;46(5):622-31. Schirra J, Wank U, Arnold R, Göke B, Katschinski M. Effects of glucagon-like peptide-1(7-36)amide on motility and sensation of the proximal stomach in humans. Gut. 2002 Mar;50(3):341-8. Schirra J, Nicolaus M, Roggel R, Katschinski M, Storr M, Woerle HJ, Göke B. Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2006 Feb;55(2):243-51. Epub 2005 Jun 28.
Starting date: February 1999
Last updated: March 31, 2015
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