The inhibitory effect of glucagon-like peptide-1 (7-36)amide on antral motility is antagonized by its N-terminally truncated primary metabolite GLP-1 (9-36)amide.
In plasma, glucagon-like peptide-1 7-36 amide (GLP-1) is rapidly degraded from the N terminus, generating the endogenous metabolite GLP-1 9-36 amide. This cleavage of GLP-1 eliminates its incretin effect, and the metabolite even may act as an antagonist. We have shown previously that GLP-1 strongly inhibited cephalic-induced antral motility in pigs. We decided, therefore, to examine the effect of GLP-1 9-36 amide, with and without GLP-1, on cephalic-induced motility in pigs. In one series of experiments, we studied the effect of three different doses of GLP-1 9-36 amide (2, 4, and 10 pmol/kg/min) on insulin-induced (hypoglycemia) antral motility in anaesthetized pigs (n = 9). In another series, we studied the effect of infusion of GLP-1 9-36 amide in two different doses (1 and 5 pmol/kg/min) in six pigs in which the antral motility was inhibited by GLP-1 7-36 amide in a dose of 2 pmol/kg/min. Plasma levels of intact GLP-1 7-36 amide and GLP-1 9-36 amide were determined using specific radioimmunoassays. Insulin-induced hypoglycemia increased the antral motility index from 0.4 +/- 0.1 to 8.3 +/- 3.5 (cm/min). The motility was constant throughout the experimental period and was absolutely unaffected by the infusion of GLP-1 9-36 amide at 10 pmol/kg/min, which resulted in a plasma concentration of 351 +/- 60 pmol/l. The inhibitory effect of GLP-1 7-36 amide on antral motility was reduced from 93 +/- 3% to 33 +/- 9% (p < 0.05) by concomitant infusion of GLP-1 9-36 amide in a dose of 5 pmol/kg/min. The metabolite GLP-1 9-36 amide has no effect on antral motility in pigs but is able to antagonize the inhibitory effect of GLP-1. Thus, an intact N terminus is essential for the gastrointestinal actions of GLP-1. Its primary metabolite may act as an endogenous antagonist.
Wettergren
A
A
Department of Gastrointestinal Surgery D, Glostrup County Hospital, University of Copenhagen, Denmark.
Wøjdemann
M
M
Holst
J J
JJ
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005768:Gastrointestinal Hormones / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005934:Glucagon; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives; D004763:Glucagon-Like Peptides; D007003:Hypoglycemia / Q000139:chemically induced; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011706:Pyloric Antrum; D013552:Swine
D005768:Gastrointestinal Hormones; D010446:Peptide Fragments; D010455:Peptides; C114437:glucagon-like peptide-1 (9-36)-amide; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon