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Isolation and physiological actions of gastric inhibitory polypeptide Pederson, Raymond Arnold

Abstract

It is known that humoral mechanisms for the inhibition of gastric secretion and motor activity operate from the duodenum. The gastrointestinal hormones cholecystokinin-pancreozymin (CCK-PZ) and secretin have been implicated as the hormones released in some of these proposed mechanisms. Despite the fact that CCK-PZ and secretin are probably involved in gastric inhibitory mechanisms, they fall short of fulfilling the original definition of enterogastrone as the inhibitory principle released from the duodenum by the presence there of fat. Impure preparations of CCK-PZ are known to stimulate H⁺ secretion in the dog when given alone and to inhibit H⁺ secretion stimulated by gastrin. Initial studies in this thesis comparing the effects of 2 purities of CCK-PZ on gastric secretion provided evidence for the existence of a gastric inhibitor distinct from CCK-PZ and secretin in partially purified CCK-PZ preparations. It was concluded from these studies that in partially purifying CCK-PZ, an inhibitory material could have been removed. This conclusion Was supported by the finding that a side fraction from the purification of CCK-PZ, with no significant CCK or secretin activity, possessed potent inhibitory activity for gastrin pentapeptide-stimulated H⁺ and pepsin secretion in the dog. The side fraction referred to in this these as EG Stage I became the starting point for several purification procedures. Purification of the inhibitory material led to the discovery that it was a polypeptide distinct in its chemical features from CCK-PZ, notably by the absence of the amino acid proline. The pure inhibitory material, gastric inhibitory polypeptide (G.I.P.), when available, was shown to possess no secretin activity, negligible CCK activity, and to have no pyrogenic or vasodepressor effects. G.I.P. was used in studies to determine its potency as an inhibitor of gastric sectretion and motor activity in the dog. Studies were carried out in which.G.I.P. was shown to be a highly potent inhibitor of H⁺ and pepsin secretion from bickel pouches and motor activity from vagally denervated antral pouches stimulated by gastrin pentapeptide and the whole gastrin molecule. Another objective was to determine if G.I.P. was effective as an inhibitor of gastric secretion against stimulants that were resistant to inhibition by CCK-PZ and secretin, e.g. histamine. Results of these experiments proved G.I.P. to be about half as effective an inhibitor of H⁺, pepsin and fundic motor activity during histamine infusion as compared with experiments in which gastrin pentapeptide was the stimulant. The range of effectiveness of G.I.P. as a gastric inhibitor was extended to vagally stimulated H⁺ and pepsin secretion with potency of inhibition equaling that found in histamine studies. As a result of structural similarities between G.I.P. and glucagon, studies were carried out to determine if G.I.P. mimicked the hyperglycemic or pancreatic inhibitory actions known to be possessed by glucagon. This was found not to be the case. In addition to inhibiting stimulated gastric secretion and motor activity, G.I.P. was shown to inhibit fundic pouch H⁺ secretion, pepsin secretion and motor activity in the unstimulated condition. It is concluded that since G.I.P. fulfills the physiological Requirements as an efficient gastric inhibitor and mimics the actions of fat in the duodenum, it is an excellent candidate for the humoral agent released from the duodenum by fat and perhaps by hydrochloric acid and hypertonic solutions. However, reservations must be held as to its status as a hormone until it is detected in blood and tissues.

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