REGULATION OF GLUCAGON-LIKE PEPTIDE-1-(7-36) AMIDE SECRETION BY INTESTINAL NEUROTRANSMITTERS AND HORMONES IN THE ISOLATED VASCULARLY PERFUSED RAT COLON

Glucagon-like peptide-1 (GLP-1) is promptly released from endocrine ce lls of the distal part of the gut after oral ingestion of a meal. To t est the possibility that hormones produced by the proximal small intes tine or transmitters of the enteric nervous system may be involved in the early phase of meal-induced GLP-1 secretion, various intestinal re gulatory peptides and neurotransmitters of the gut were administered i ntraarterially in the isolated vascularly perfused rat colon preparati on. The release of GLP-1 in the portal effluent was measured by a spec ific RIA. Intraarterial infusion of glucose-dependent insulinotropic p eptide (GIP) over the concentration range 0.25-1 nM evoked a dose-depe ndent release of GLP-1, with a maximal response of 350% of the basal v alue. Tetrodotoxin did not modify the GIP-induced release of GLP-1. Se cretin or cholecystokinin did not stimulate the secretion of GLP-1. Bo mbesin (10(-9)-10(-7) M) provoked a dose-dependent release of GLP-1, c onsisting of an early peak, followed by a sustained response. Calciton in gene-related peptide (5 x 10(-8) M) induced a dramatic rise of GLP- 1 immunoreactivity in the portal effluent (peak at 800% of the basal v alue 10 min after the start of infusion). Similarly, the beta-adrenerg ic agonist isoproterenol at concentrations of 10(-7) and 10(-6) M prov oked a pronounced release of GLP-1 (peak at 500% of the basal value wi th 10(-6) M isoproterenol). Finally, the muscarinic cholinergic agonis t bethanechol at a concentration of 10(-4) M evoked a gradual increase in GLP-1 immunoreactivity, which reached a maximal value (900% over b asal) at the end of the 30-min infusion period. The lowest concentrati on of bethanechol used in the present study (10(-5) M) did not increas e portal GLP-1 immunoreactivity over the basal value. Tetrodotoxin did not modify the bethanechol-, isoproterenol-, calcitonin gene-related peptide-, or bombesin-induced GLP-1 release. In conclusion, the presen t study conducted with the isolated vascularly perfused rat colon show s that there are interactions between the two most potent incretins, G IP and GLP-1, probably through an enteroendocrine pathway. Additionall y, several transmitters of the gut are potent stimulants of GLP-1 rele ase and, therefore, represent potential tools in the treatment of the noninsulin-dependent diabetes mellitus.