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Sponsors and Collaborators: |
Ludwig-Maximilians - University of Munich German Research Foundation Philipps University Marburg Medical Center |
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Information provided by: | Ludwig-Maximilians - University of Munich |
ClinicalTrials.gov Identifier: | NCT00468091 |
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.
Condition | Intervention | Phase |
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Digestive Physiology Gastrointestinal Motility Gastrointestinal Hormones Glucagon-Like Peptide 1 Exendin (9-39) |
Drug: exendin(9-39)amide Drug: atropine |
Phase I |
Study Type: | Interventional |
Study Design: | Diagnostic, Randomized, Double-Blind, Placebo Control, Crossover Assignment, Pharmacodynamics Study |
Official Title: | Regulation of Antro-Pyloro-Duodenal and Proximal Gastric Motility by GLP-1: Involvement of Cholinergic Pathways |
Enrollment: | 10 |
Study Start Date: | February 1999 |
Study Completion Date: | September 2000 |
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.
Ages Eligible for Study: | 18 Years to 65 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | Yes |
Inclusion Criteria:
Exclusion Criteria:
Germany | |
Clinical Research unit, Dept. of Internal Medicine II - Großhadern, University of Munich | |
Munich, Germany, 81377 |
Principal Investigator: | Joerg Schirra, MD | Clinical Research Unit, Dept. of Internal Medicine II, University of Munich |
Study ID Numbers: | MATEX, DFG Ar149/1-2, DFG 527/5-2 |
Study First Received: | April 30, 2007 |
Last Updated: | April 30, 2007 |
ClinicalTrials.gov Identifier: | NCT00468091 |
Health Authority: | Germany: Federal Institute for Drugs and Medical Devices |
GLP-1 exendin(9-39) atropine human motility |
Glucagon-Like Peptide 1 Atropine |
Parasympatholytics Respiratory System Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Cholinergic Antagonists Physiological Effects of Drugs Anti-Asthmatic Agents Cardiovascular Agents Cholinergic Agents Pharmacologic Actions |
Muscarinic Antagonists Adjuvants, Anesthesia Mydriatics Autonomic Agents Therapeutic Uses Anti-Arrhythmia Agents Peripheral Nervous System Agents Central Nervous System Agents Bronchodilator Agents |