PEPTIDE YY--COLONIC GASTRIC AND PANCREATIC INHIBITION

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The goal is to establish the newly discovered ileo-colonic peptide, Peptide YY (PYY), as a true hormone. As PYY has not been approved for use in human subjects, studies will be performed in dogs. The first series of experiments will examine mechanisms of release of PYY. In particular, we will determine whether neural or hormonal messages from the upper intestine determine PYY release or whether direct contact of nutrients with the ileo-colonic mucosa is a necessary prerequisite for release. In the next series of experiments, we will examine the effects of exogeneously infused Peptide YY on th pancreatic secretory response to secretin, cholecystokinin and sham feeding. Other studies will examine the effects of PYY on gastric emptying of liquid and solid meals. In these studies circulating levels of PYY observed during infusion of exogeneous PYY will be compared to those observed after a meal and after the intestinal perfusion of oleic acid to determine if these effects are pharmacological or physiological. We recently demonstrated that PYY specifically inhibits the cephalic phase of acid secretion. To determine if PYY's biological actions are vagal dependent we will examine the effects of vagotomy on PYY's ability to inhibit gastric and pancreatic secretion. In other experiments we will perfuse the ileum and colon with oleic acid and monitor the effects on pancreatic and gastric secretion and on plasma peptide YY concentrations. Additional animals will be prepared with intestinal cannulas so that intestinal contents can be diverted above the ileum to determine the effects of ileo-colonic exclusion on meal stimulated gastric and pancreatic secretion and PYY release. Blood levels of PYY observed under each experimental condition will then be reproduced by infusion of exogenous PYY to determine if PYY explains the altered secretion after ileal perfusion of oleic acid or ileal bypass. Metabolic clearance studies will then be performed to determine if PYY has a metabolic half life comparable to that of established gastrointestinal hormones. Finally, canine PYY will be extracted, purified and the amino acid sequence determined. These studies will determine whether PYY has a physiological or pathophysiological role as a modulator of gastric and pancreatic secretion. They should establish PYY as an enterogastrone with unique characteristics. Finally, they will determine if PYY is the ileo-colonic pancreatic inhibitor, the "pancreatone", or "anti-CCK hormone" described by others.