Gastrointestinal Motility Clinical Trial
Official title:
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.
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.
;
Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Double-Blind, Primary Purpose: Diagnostic
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