GLUCAGON-LIKE PEPTIDE-1-(7-36) AMIDE AND PEPTIDE YY MEDIATE INTRADUODENAL FAT-INDUCED INHIBITION OF ACID-SECRETION IN DOGS

Intraduodenal fat inhibits gastric acid secretion via the release of o ne or more hormonal enterogastrones thought to arise from ileocolonic mucosa. This study determined whether glucagon-like peptide-1 (GLP-1)- (7-36) amide and peptide YY (PYY), colocalized in L cells found in the ileum, mediate intraduodenal fat-induced inhibition of stimulated gas tric acid, and evaluated the influence of cholecystokinin-A (CCK-A) re ceptor activation. Gastric acid secretion in response to duodenal perf usions of 8% peptone was measured in conscious dogs with gastric and d uodenal cannulas. Intraduodenal administration of a 10% fat emulsion s uppressed gastric acid secretion by 72 +/- 4% (P < 0.001) and increase d plasma levels of GLP-1 and PYY by 44 +/- 5 and 46 +/- 4 fmol/ml, res pectively (both P < 0.01). Pretreatment with the CCK-A receptor antago nist MK-329 completely reversed the inhibition of gastric acid by fat, suppressed rises of plasma GLP-1 (maximum change, 23 +/- 4 fmol/ml), and reduced plasma PW responses to baseline. Intravenous infusions of 50 pmol/ kg.h GLP-1 or PYY, which reproduced plasma elevations after i ntraduodenal fat, inhibited gastric acid secretion by 66 +/- 5% and 51 +/- 6%, respectively (both P < 0.01); coinfusions of GLP-1 and PYY ab olished gastric acid secretion (P < 0.001) without influencing plasma gastrin or somatostatin. Pretreatment with 1500 pmol/kg.h of the GLP-1 antagonist exendin-(9-39) amide did not alter the magnitude of inhibi tion of gastric acid caused by exogenous GLP-1. These results indicate that GLP-1 and PYY released by intraduodenal fat, in part through CCK -dependent pathways, are major enterogastrones in dogs. This inhibitor y action occurs independent of circulating concentrations of somatosta tin and gastrin and appears to involve a GLP-1 receptor distinct from that mediating incretin effects.