Pancreatic polypeptide response to insulin in duodenal ulcer. Different levels in accordance with ulcer activity and its response to treatment.

Pancreatic polypeptide is said to be a marker of vagal tone in duodenal ulcer. To determine whether pancreatic polypeptide levels are related to the course of duodenal ulcer, we studied acid and pancreatic polypeptide responses to insulin in 80 patients with duodenal ulcer disease: 40 with unoperated duodenal ulcer and 40 with proximal vagotomy. Data were analysed in accordance with the presence of an ulcer (active disease) and, when present, in accordance with the ulcer healing on medical treatment (cimetidine, 1 g/day for 4 weeks). In both groups acid and pancreatic polypeptide responses to hypoglycaemia were slightly correlated (r = 0.38) (p less than 0.05). The basal pancreatic polypeptide level was higher in patients with active disease than in those with inactive disease, who had a basal level similar to that of normal subjects of the same age range. Like the insulin-stimulated acid secretion, the pancreatic polypeptide response to insulin hypoglycaemia was higher in patients with active disease than in those with inactive disease (p less than 0.05): 26.1 +/- 3.9 versus 20.1 +/- 4 nmol/l/120 min, respectively, in unoperated patients and 34.8 +/- 2.2 versus 24.3 +/- 2.5 nmol/l/120 min, respectively, after proximal vagotomy. In active disease the pancreatic polypeptide response to insulin hypoglycaemia was higher in subjects whose ulcer did not heal further after cimetidine therapy than in those whose ulcer did. These data suggest that the pancreatic polypeptide response to insulin is an indicator of duodenal ulcer activity and is related to the treatment efficacy. These relationships are partly mediated by increased vagal tone.

Persistence of circadian rhythms in gastric acid, gastrin, and pancreatic polypeptide secretions despite loss of cortisol and body temperature rhythms in man under stress.

During organic stress, severe dysfunctions of fundamental biological phenomena, such as modification of vagal tone, have been described. These dysfunctions could induce changes in the rhythm of acid secretion and/or its hormonal control. We therefore analyzed the effects of acute respiratory failure on the 24 h variations in intragastric pH, serum gastrin, and pancreatic polypeptide levels, taken as a marker of vagal tone. Body temperature and plasma cortisol circadian rhythms were used as marker rhythms. Twelve patients with chronic obstructive pulmonary disease complicated with acute respiratory failure were studied before and during continuous enteral nutrition; half of the patients received ranitidine, a H2 blocker. During the 3 days of the study, intragastric pH was below 2.5 for only one third of the time. No difference was observed between the placebo and the ranitidine groups. Plasma pancreatic polypeptide was within normal ranges despite increased cortisol levels. Gastrin levels reflected changes in intragastric pH over the 24 h time frame and were noted to increase during ranitidine and enteral nutrition. Despite the loss of cortisol and body temperature circadian rhythmicity all throughout the study, circadian rhythms were maintained or restored during the different therapeutic regimens for intragastric pH, serum gastrin, and pancreatic polypeptide levels. Moreover, an ultradian rhythm for gastrin before any treatment, a circadian rhythm for intragastric pH on enteral nutrition, a circadian rhythm for intragastric pH, plasma gastrin and plasma pancreatic polypeptide on ranitidine regimen were observed. Thus during acute respiratory failure, certain physiological circadian rhythms persisted despite the disappearance of "marker" rhythms. Furthermore, these rhythms for digestive secretions could be pharmacologically restored.

[Histologic aspect of the human gastric mucosa: relation to gastrin and somatostatin cells and the intraluminal secretion of these peptides]. / Aspect histologique de la muqueuse gastrique humaine: relations avec les cellules à gastrine et à somatostatine et la sécrétion intraluminale de ces peptides.

Fifty-eight subjects including controls, patients with duodenal ulcer, non-operated or treated with a superselective vagotomy underwent endoscopic fundic and antral biopsies. Histologic classification of the two mucosae was performed. We examined the relationship between the histologic grade of gastritis in the two mucosae, then between the histologic aspect of the antral mucosa and antral gastrin-and somatostatin-cell densities, the basal intraluminal secretion of gastrin and somatostatin. There was a significant correlation between the histologic aspect of fundic or antral mucosa and the age of patients, except in the case of vagotomized patients. Fundic and antral histologic patterns were also correlated in each patient, except for vagotomized. Gastrin and somatostatin cell densities showed no variation in function of the degree of inflammation of non atrophic gastritis. These cell densities showed a tendency to decrease in atrophic gastritis, especially when intestinal metaplasia was present. Intraluminal gastrin secretion was increased in patients with mild atrophic gastritis (p less than 0.05 to p less than 0.02) in comparison with those whose histology was roughly normal. It was also increased in severe atrophic gastritis. The highest intraluminal secretion of somatostatin was observed in patients with mild atrophic gastritis while this secretion fell noticeably in those showing severe atrophic gastritis, as compared to the other groups. This work seems to suggest a relationship between intraluminal peptides and the evolution of gastritis. While results are still preliminary, they do not indicate that these peptides, thus released, play any pathophysiologic role.

Sensitivity, specificity and predictive values of the secretin infusion test in the diagnosis of gastrinoma.

From 1974 to 1981, 55 patients, 18 with Zollinger-Ellison syndrome (ZES) histologically confirmed and 37 patients with duodenal ulcer (DU) without pylorostenosis were followed for a minimal period of 5 years. The diagnostic values of a) basal acid output (BAO mEq/h); b) 60 min acid output after secretin infusion, 3 CU-GIH/kg, (MAO-SE mEq/h); c) basal serum gastrin (BSG pg/ml: mean of 4 gastrin determinations) and d) serum gastrin after secretin (SG-SE pg/ml: mean of 4 gastrin determinations during secretin infusion) were calculated. Cut off point values of 100 p. 100 specificity (i. e. no DU patient reached these values) with a positive predictive value of 100 p. 100 (i. e. probability for gastrinoma when this cut off point was attained) were BAO greater than 26 mEq/h, MAO-SE greater than 18 mEq/h, BSG greater than 221 pg/ml, SG-SE greater than 186 pg/ml. The sensitivities of these parameters (i. e. percent of ZES which reached the given cut off point) were respectively (p. 100): 39, 78, 72 and 94. Ranking these parameters according to their own discriminative value expressed by R2 (square correlation coefficient) gave SG-SE, R2 = 0.559; BSG, R2 = 0.508; MAO-SE, R2 = 0.456; BAO, R2 = 0.414. The most discriminative association of 2 variables was SG-SE and MAO-SE (R2 = 0.650). Association of SG-SE, MAO-SE and BAO or BSG (or BAO and BSG) did not increase significantly the discrimination between ZES and DU (R2 = 0.672).

A comparative evaluation of secretin bolus and secretin infusion as secretin provocation tests in the Zollinger-Ellison syndrome.

GIH secretin bolus (2 CU/kg) and infusion (3 CU/kg/h) have been randomly compared in 9 ZES patients and 10 age-matched DU patients. Serum gastrin and gastric acid variations were studied before and after either mode of secretin administration in the same individuals. Plasma secretin modifications were monitored in parallel. In both ZES and DU, secretin bolus and infusion induced similar gastrin responses (maximal changes and integrated responses). However, secretin infusion had a greater effect on acid output than bolus: larger inhibition in DU and larger increase in ZES. The additive diagnostic value of gastric acid secretion study during a secretin provocation test, as already reported, favors the use of 3 CU/kg/h secretin infusion over that of 2 CU/kg secretin bolus.

Detection of tyrosine-specific protein kinases with gastrin as exogenous substrate.

Gastrin was recently shown to be phosphorylated on its single tyrosine by the epidermal growth factor (EGF)-stimulated tyrosine protein kinase (TPK). The TPK previously detected in the murine lymphoma (LSTRA) induced by the Moloney murine leukemia virus phosphorylates gastrin, the apparent Km is 65 microM and the maximum rate 1900 pmol/min per mg; the kinase is more efficient with MnCl2 than with MgCl2, is stimulated by NaVO3 and inhibited by ZnCl2. Gastrin phosphorylation is observed only when a TPK is expressed by the cell: extracts of fibroblasts infected with a temperature-sensitive mutant of the Rous sarcoma virus had no gastrin kinase activity when grown at the non-permissive temperature whereas cells grown at the permissive temperature were transformed and disclosed a clear gastrin kinase activity. Gastrin kinases were detected in various transformed cells: human lymphomas, K562 cells, cells from a patient with acute proliferative leukemia, and normal cells: human T and B lymphocytes.

[Release of pancreatic polypeptide in response to the intragastric administration of a meal is not different in duodenal ulcer patients and normal subjects]. / La libération de polypeptide pancréatique en réponse à l-administration intra-gastrique d'un repas n'est pas différente chez des ulcéreux duodénaux et des sujets normaux.

The high basal and meal-induced acid secretions in duodenal ulcer patients has led to the concept that vagal hyperactivity is a common factor in the pathogenesis of peptic ulcer. For these reasons, since pancreatic polypeptide secretion is known to be under vagal control, we studied the pancreatic polypeptide release after intragastric administration of two protein meals (10 and 20 g protein in 400 ml) in 18 duodenal ulcer patients and in 17 normal subjects. After a 10 g protein meal was administered, gastric pH was either maintained at pH 4.5 or allowed to decrease. The 20 g protein meal induced a higher pancreatic polypeptide release than did the 10 g protein meal (p less than 0.05): the integrated pancreatic polypeptide responses were 1.07 +/- 0.5 and 3.21 +/- 0.58 nmol/l/60 min respectively in the duodenal ulcer group and 0.46 +/- 0.21 and 2.67 +/- 0.69 nmol/l/60 min respectively in the control group. On the other hand, the responses to the two protein meals in duodenal ulcer patients were not different from those obtained in normal subjects, despite the higher meal-induced acid secretions in the duodenal ulcer group. pancreatic polypeptide increase was not larger when gastric pH was fixed than when it was allowed to decrease, 0.56 +/- 0.21 and 1.7 +/- 0.63 nmol/l/60 min respectively in normal subjects and 1.07 +/- 0.5 and 1.07 +/- 0.49 nmol/l/60 min respectively in duodenal ulcer patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal pancreatic polypeptide release by secretin infusion in Zollinger-Ellison syndrome.

In 28 patients with the Zollinger-Ellison syndrome (ZES), 26 studied before and two after tumor excision, and in 26 age-matched control patients with duodenal ulcer (DU), plasma pancreatic polypeptide and serum gastrin concentrations were studied before, during, and after infusion of pure secretin (3 CU/kg/hr). In 21 ZES patients, gastric acid output was simultaneously studied. Fasting pancreatic polypeptide concentrations were over 300 pmol/liter in five of 26 gastrinomas. In DU, secretin caused a nonsignificant increase in plasma pancreatic polypeptide concentration and markedly decreased gastric acid output. In ZES, however, it resulted in a marked increase of both plasma pancreatic polypeptide concentration and gastric acid output. Basal and post secretin pancreatic polypeptide concentrations showed no correlation with gastric acid output, serum gastrin levels, or the age of the subjects, in DU patients as well as in ZES. These concentrations were not different in ZES patients who had a vagotomy compared to nonvagotomized ZES patients. Furthermore, the pancreatic polypeptide response to intravenous secretin was abolished by gastrinoma excision.

[Secretion of pancreatic polypeptide in cats in response to different stimuli; correlation with gastric acid secretion]. / Etude chez le chat de la sécrétion de polypeptide pancréatique en réponse à différents stimuli; corrélation avec la sécrétion gastrique acide.

The pancreatic polypeptide response to a meal depends on various mechanisms, which are only partly understood. The aim of this study was to define whether humoral factors and nutrients which modulate postprandial gastric acid secretion play a role in the regulation of pancreatic polypeptide secretion. Our study was performed in the cat, a species in which pancreatic polypeptide release has never been explored. The animals were provided with a gastric fistula and a Heidenhain pouch and received, in a random order, mixed liver (50 g) per os or different nutriments which were introduced directly into the gastric fistula in identical final volumes: 50 g mixed liver; 1.5 to 12 g oligopeptides; or 2 g of triglycerides or glycogen. Acid output and pancreatic polypeptide secretion were measured over 150 min. In the cat as in dog and man, a mixed meal induced a five to ten-fold increase of plasma pancreatic polypeptide. The protein fraction of the meal was the most potent stimulus for release of this peptide and the pancreatic polypeptide response to protein seemed to be dose-related. The lipid and carbohydrate components of the meal were only weak stimulants. In the cat, a central vagal stimulation is effective on pancreatic polypeptide release, as on gastric acid secretion, since 2-deoxyglucose stimulated both secretions (about 15 p. 100 of maximal response to a meal). The integrated pancreatic polypeptide release and the Heidenhain pouch acid secretion in response to nutriments were correlated during the 30-120 min period.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic administration of bombesin stimulates antral gastrin cell proliferation in the rat.

Bombesin tetradecapeptide, administered in gelatin twice daily for 1 wk, significantly increased the antral gastrin content in rats by stimulating antral gastrin cell proliferation. The labeling index of gastrin cells after five daily injections of [3H]thymidine given during bombesin treatment was significantly enhanced as compared with controls, while no modification in the pattern of antral somatostatin cell labeling was revealed. Total antral gastrin cell population at the end of bombesin treatment also increased significantly. Morphometric measurements at the electron microscope level showed that the mean size of gastrin cell in the bombesin-treated group was the same as in the control group. The size of gastrin secretory granules and their number per cell did not change. The present findings demonstrate that chronic administration of bombesin induces gastrin cell hyperplasia in the rat.

Metiamide treatment in five patients with Zollinger-Ellison syndrome.

Five patients with Zollinger-Ellison syndrome received metiamide per os in doses ranging from 600 to 1,200 mg/day for a minimum period of 2 weeks. Drug produced an inhibition of basal gastric acid secretion ranging from 5 to 100% with relief of symptoms. Survey of patients during and after metiamide course showed sometimes a prolonged antisecretory effect up to 26 days after the end of treatment or, on the contrary, a reduced drug activity in spite of increasing doses.

In vitro secretion of gastrin, insulin, and glucagon in tissue cultures of pancreas from a child with neonatal intractable hypoglycemia.

Small pieces of pancreatic tissue were obtained at surgery from a subtotal pancreatectomy performed in a 45-day-old child suffering from intractable neonatal hyperinsulinic hypoglycemia. Histological examination was performed using aldehyde fuchsin, Grimelius', and Hellerström-Hellman's stainings, and immunoperoxidase labeling of insulin and gastrin. The pancreatic tissue before explantation showed numerous and sometimes hyperplastic islets, together with isolated insulin-, glucagon-, and gastrin-containing cells scattered among the exocrine tissue, in aspects similar to "B cell nesidioblastosis." These features could be interpreted as an acinoinsular transformation and/or an embryonic malformation. Extralobular endocrine islet formation by budding from ductular structures was evoked, suggesting the persistency of embryonic properties. The pieces were cultivated on rooster plasma coagulum covered with culture medium. In vitro, endocrine cells survived for 43 days, with outgrowth from the explant and with retention of their secretory abilities. After each medium renewal, radioimmunoassays were performed on the culture medium; they showed that insulin and glucagon secretions decreased with time. On the contrary, secretion of immunoreactive gastrin progressively increased, and kept up to 43 days, with subcultures. Some explants developed in a peculiar way, outgrowing as epithelial layers rich in gastrin-secreting cells as indicated by radioimmunoassays performed after they were reexplanted.