Effects of Exendin(9-39) on Gastroduodenal Motility
Condition: Digestive Physiology; Gastrointestinal Motility; Gastrointestinal Hormones; Glucagon-like Peptide 1; Exendin (9-39)
Study type: Interventional
Phase: Phase 1

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.
    

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.
    

Intervention name(s): exendin(9-39)amide; atropine
Intervention type(s): Drug; Drug
Intervention MeSH terms: Atropine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double
Primary purpose: Diagnostic
Keywords: GLP-1; exendin(9-39); atropine; human; motility