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Glucagon-Like Peptide-1-(7–36) Amide and Peptide YY Mediate Intraduodenal Fat-Induced Inhibition of Acid Secretion in Dogs¹

Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario, Canada

Address all correspondence and requests for reprints to: Dr. G. R. Greenberg, Room 6356, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

Intraduodenal fat inhibits gastric acid secretion via the release of one or more hormonal enterogastrones thought to arise from ileo-colonic 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 gastric acid, and evaluated the influence of cholecystokinin-A (CCK-A) receptor activation. Gastric acid secretion in response to duodenal perfusions of 8% peptone was measured in conscious dogs with gastric and duodenal cannulas. Intraduodenal administration of a 10% fat emulsion suppressed gastric acid secretion by 72 ± 4% (P < 0.001) and increased plasma levels of GLP-1 and PYY by 44 ± 5 and 46 ± 4 fmol/ml, respectively (both P < 0.01). Pretreatment with the CCK-A receptor antagonist 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 PYY responses to baseline. Intravenous infusions of 50 pmol/kg·h GLP-1 or PYY, which reproduced plasma elevations after intraduodenal fat, inhibited gastric acid secretion by 66 ± 5% and 51 ± 6%, respectively (both P < 0.01); coinfusions of GLP-1 and PYY abolished 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 inhibition 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 inhibitory action occurs independent of circulating concentrations of somatostatin and gastrin and appears to involve a GLP-1 receptor distinct from that mediating incretin effects.

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