Despite earlier indirect evidence that an antral chalone exists, no such inhibitor has been found in antral extract. Recently, interest in the question of an antral inhibitory mechanism has been revived by studies that showed that for a given rise in serum gastrin caused by antral distension, the response of both the innervated and denervated stomach is greatly enhanced by vagal denervation of the antrum. While this study suggested a neuro-humoral character of the antral inhibitory mechanism, it gave no indication as to the source of the inhibitor. Subsequent studies, however, suggested that neither the antrum nor the CNS was the source for this inhibitor. The initial aim of this study was to investigate the fundus as a possible source of the inhibitor by studying the effect of proximal gastric vagotomy on the antral inhibitory mechanism initiated by distension. The results gave clear indication that the inhibitor was indeed released from the fundus; indeed, the antral inhibitory mechanism was in reality a fundic one. Once the fundus was shown to be the source of the inhibitor, it was necessary to establish whether this inhibitor did in fact reside in the fundic mucosa. Four dogs were prepared with a denervated fundic pouch (or Heidenhain pouch, HP), and a fistula of the main, innervated stomach (gastric fistula, GF). The acid secretory responses of both the HP and GF to graded doses of pentagastrin and histamine was studied. In addition both the secretion of acid and the response of immunoreactive gastrin in the blood in response to a standard meal of 15% liver extract was studied. All these experiments were repeated after excision of the fundic mucosa of the main stomach. The results show that excision of the fundic mucosa reduced the GF acid secretion to the stimuli by 85-100%. By contrast, the maximal HP acid secretion increased by 247% in response to pentagastrin and 200% in response to histamine. The increase in the response to submaximal doses of these exogenous stimuli was even greater. Similarly, the peak 30 minutes HP output in response to feeding increased by 418%. Fundic mucosal excision also resulted in the increase in both basal (from 36±3 to 248±37 pg/ml) and food-stimulated response (from 168±12 preoperatively to 392±49 pg/ml postoperatively). Since the intragastric pH was held constant at 5.5 during the meal tests both before and after the operation, the augmented gastrin response could not be attributed to reduced acid secretion caused by excision of the fundic mucosa. From these studies it can be concluded that: (1) antral distension releases an inhibitor from the fundus; (2) excision of the fundic mucosa results in increased response of the HP to both submaximal and maximal doses of pentagastrin and histamine indicating that both the sensitivity of the oxyntic cell and parietal cell mass has increased; (3) excision of the fundic mucosa results in increased basal and food-stimulated gastrin response independent of the pH of the meal suggesting removal of an inhibitor of gastrin release. / Surgery, Department of / Medicine, Faculty of / Graduate

(A) Gastric Secretion The present study was performed to investigate the canine post-pancreatic duct ligation GIP secretion in response to fat ingestion using a meat meal mixed with unhydrolyzed or hydrolyzed whipping cream, and to determine whether GIP plays a role in the production of hyperacid secretion in the pancreatic duct ligated dogs. Four mongrel female dogs were prepared with Heidenhain pouch (HP) and gastric fistula (GF), and daily acid secretion from the HP was measured before and after pancreatic duct ligation (PDL). HP acid output, serum immunoreactive gastrin (IR-Ga) and serum immunoreactive gastric inhibitory polypeptide (IR-GIP) concentrations during five hours following oral ingestion of a meat meal alone, a meat meal mixed with 125g of unhydrolyzed cream and meat meal mixed with 125g of hydrolyzed cream were measured before and after PDL. Twenty four hour HP acid outputs increased significantly in each of the four dogs after PDL. Five hour HP acid outputs in response to a meat meal alone and a meat meal plus unhydrolyzed cream were modestly increased, while those in response to a meat meal plus hydrolyzed cream were rather reduced after PDL. Serum IR-Ga responses to all stimulants were lowered after PDL and those to meat meal plus hydrolyzed cream lowered most markedly. Serum IR-GIP responses to a meat meal alone were significantly increased, while those to a meat meal plus unhydrolyzed and hydrolyzed cream were reduced. The results of the present study demonstrate serum IR-GIP in response to a meat meal is increased by PDL in dogs, suggesting augmented acid juice passing into the intestinal lumen is responsible for the increased GIP response. It is indicated that hypo-secretion of GIP is not the cause of hypersecretion of gastric acid in the PDL dogs. (B) Glucose Metabolism. Functional alteration in glucose homeostasis especially concerning the early onset of diabetes after PDL was studied in dogs. Intravenous (i.v.) and intragastric glucose tolerance tests were performed at two to ten weeks and two weeks after PDL respectively. Serum glucose, IRI, and IR-GIP in response to a meat meal with and without unhydrolyzed or hydrolyzed fat were estimated at six weeks after PDL. Significantly impaired glucose tolerance and early phase IRI secretion after i.v. glucose were shown at two to ten weeks after PDL. Intragastric glucose load revealed delayed pattern of serum glucose and IRI (no evidence of glucose intolerance or diminished IRI secretion), indicating decreased gastric motility after PDL. Serum IR-GIP response to intragastric glucose load was not attenuated by the operation but showed a similar pattern to IRI response. Serum IRI responses to meat meals with and without unhydrolyzed or hydrolyzed cream were impaired after PDL. It is indicated that dogs after PDL show early onset (two to ten weeks) of diabetes, i.e. blunted early phase insulin secretion, 2 the mechanism of GIP secretion as an insulinotropic enterohormone remains intact after PDL if sufficient stimulants are given. / Surgery, Department of / Medicine, Faculty of / Graduate

Part I Inhibition of Gastric Acid Secretion Fat in the small bowel is a powerful inhibitor of gastric acid secretion. The gastric inhibitory agent(s) liberated from intestinal mucosa by the presence of fat has been named enterogastrone. Gastric inhibitory polypeptide (GIP), has been considered a candidate for enterogastrone. GIP is released into the circulation by infusion of fat into the proximal small bowel and inhibits gastric acid secretion under select experimental conditions. It has been proposed that the release of somatostatin, a potent inhibitor of acid secretion, may mediate the gastric inhibitory action of GIP. Recently, monoclonal antibodies raised to both GIP and somatostatin have been produced. The suitability of these antibodies for the study of the physiological roles proposed for their respective peptides is not known. This study examined the inhibitory action of GIP and somatostatin on gastric acid secretion in the rat and in man. GIP was found to be a weak inhibitor of meal-stimulated gastric acid secretion in man when given in supraphysiological doses. When administered at a dose which produces less than the normal maximal physiological plasma level, GIP had little effect on the acid secretory response to the meal and no effect on either plasma gastrin or plasma SLI concentrations. In the rat, infusion of GIP produced a 60% reduction of meal-stimulated acid secretion, independent of changes in serum gastrin release. Intraduodenal infusion of oleic acid in the rat reduced the gastric acid secretory response to a liver extract meal by 80% without affecting serum gastrin levels. A humoral gastric inhibitory agent, or "enterogastrone", was demonstrated in the portal blood of the rat following fat infusion. Intravenous infusion of portal serum, which had been collected during an intraduodenal infusion of fat, reduced meal-stimulated acid secretion in a second animal. A comparison of the inhibition of gastric acid secretion produced by intraduodenal infusion of either glucose or oleic acid with the release of IR-GIP in the portal serum was performed. The inhibitory effect of an intraduodenal fat infusion could not be explained by plasma IR-GIP. The release of GIP was not found to play a significant role in the mechanism for gastric inhibition by intestinal fat. Part II Monoclonal antibodies as Probes of Humoral Inhibitors of Gastric acid secretion The ability of recently produced monoclonal antibodies to block in vivo the inhibitory action of exogenous GIP and somatostatin on gastric acid secretion was examined. Anti-GIP monoclonal antibody demonstrated a high affinity for GIP when compared to the polyclonal rabbit antiserum R07 in the ELISA. When administered either as an intravenous bolus, or after incubation with GIP for 1 hour at 37°C, the antibody was unable to block the inhibitory effect of a GIP infusion on meal-stimulated gastric acid secretion in the rat. Monoclonal antibody 3.65H may not be suitable for the study of the role of endogenously released GIP. Two anti-somatostatin monoclonal antibody clones 58 and 510, when given as intravenous boluses, blocked the inhibitory action of exogenous somatostatin on meal-stimulated gastric acid secretion in the rat. The antibody clone S10 however, had no effect on the inhibitory action of exogenous GIP on gastric acid secretion. Although both monoclonal antibodies S8 and SIO effectively prevented the gastric inhibitory effect of infused somatostatin, the ability to block the physiological action of endogenously released gastric somatostatin remains to be determined. / Surgery, Department of / Medicine, Faculty of / Graduate