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

Abstract

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.