Pathomorphologic, biochemical, and diagnostic aspects of gastrinomas (Zollinger-Ellison syndrome).

The clinical symptomatology of the Zollinger-Ellison syndrome and the pathologic anatomy of gastrinomas are reviewed. Experience with 17 patients with the Zollinger-Ellison syndrome is presented with special reference to stimulation tests (secretin, glucagon, calcium infusion, test meal) and to localization and immunohistologic, ultrastructural, and biochemical findings in gastrinomas. Multiple hormone production by the tumors is frequent. The ultrastructure and the Sephadex G-50 gel filtration patterns of immunoreactive gastrin in sera and tumors are not uniform and are not related to localization of the tumors in the pancreas or duodenum or to the gastrin concentration. Hyperplasia of the pancreatic islets is a frequent finding in gastrinoma patients, suggesting that hypergastrinemia may stimulate islet growth.

Guar by-product improves carbohydrate tolerance in rats.

These studies were designed to assess the effect of guar by-product (GBP) upon carbohydrate tolerance in rats. Both 1% and 10% GBP suspensions administered immediately before a glucose challenge (1 g/kg body weight) caused a 31% reduction in the integrated plasma glucose response area during a 180 min test. Because 10% GBP caused a flattened glucose response curve, it was studied further. Ten percent GBP caused a similar reduction in plasma glucose during a 360-minute test; similar plasma insulin levels were measured in both 0% and 10% GBP groups throughout the 360-minute test. Ten percent oat bran and 10% soy bran had no effect upon plasma glucose responses. Ten percent GBP was effective in lowering glycemic excursions after sucrose and starch challenges. Rats fed pellet fractions from water and acid treated GBP had the lowest plasma glucose excursions after a glucose challenge; simulated gastric juice treatment of GBP reduced the hypoglycemic activity and simulated pancreatic juice treatment destroyed it. These studies demonstrate the ability of GBP suspensions to significantly reduce plasma glucose excursions after carbohydrate challenge.

Motilin and human pancreatic polypeptide measured in CSF from alcoholic and non-alcoholic neurological patients.

Thirty-one CSF samples from alcoholics and non-alcoholic neurological patients were assayed for immunoreactive motilin and human pancreatic polypeptide (HPP). Both peptides were detected in all samples. Alcoholics without liver disease had significantly higher levels of motilin and lower levels of HPP than neurological controls.

PHI structural requirements for potentiation of glucose-induced insulin release.

Immunoreactive PHI was detected in rat pancreas. The potentiating effect of 10(-9) M PHI upon insulin release from the isolated perfused rat pancreas was significant and most consistent when 250 mg% glucose was present in the perfusion medium. PHI(1-15) retained a substantial potentiating effect on insulin release, while PHI(14-27) was essentially inactive. Replacement of amino-terminal decapeptide portion of the PHI molecule with the corresponding part of VIP resulted in a drastic decrease of the potentiating effect of PHI on insulin release. 10(-8) M PHI(14-27) substantially diminished the potentiation by 10(-9) M PHI while PHI(1-15) was without an inhibitory effect. The present results indicate that the PHI active site for potentiation of glucose-induced insulin release resides in the amino-terminal segment of the molecule but requires the carboxyl terminal segment primarily for binding to exhibit full biological activity.

A qualitative comparison of canine plasma gastroenteropancreatic hormone response to bombesin and the porcine gastrin-releasing peptide (GRP).

The effect on plasma gastroenteropancreatic hormone levels on infusing the porcine gastrin-releasing peptide and bombesin into dogs demonstrated no qualitative difference in the spectrum of activity of the two peptides. Sustained elevation in plasma immunoreactive gastrin, pancreatic polypeptide, enteroglucagon, gastric inhibitory polypeptide, pancreatic glucagon and transient elevations in plasma insulin were seen during infusions of both peptides. The similar spectrum of activities and the structural homology between the two peptides suggests that the porcine gastrin releasing peptide is the porcine counterpart of the amphibian peptide bombesin.

Motilin, human pancreatic polypeptide (HPP) and gastrin plasma concentrations in fasting subjects.

Motilin, human pancreatic polypeptide (HPP) and gastrin plasma concentrations have been determined in 196 fasting subjects ranging in age from the third to ninth decade. Detailed descriptions of the motilin, HPP and gastrin radioimmunoassays are presented. Plasma motilin concentrations ranged from undetectable to 1253 ng/L with a median value at 157 ng/L. Age and sex did not influence plasma motilin concentrations. Plasma HPP concentrations ranged from undetectable to 1564 ng/L with a median value at 142 ng/L. Plasma HPP concentrations increased significantly with age; males generally had higher concentrations than females. Plasma gastrin concentrations ranged from undetectable to 1658 ng/L with a median value of 21 ng/L. Age and sex did not influence plasma concentrations. These data establish ranges for plasma motilin, HPP and gastrin in fasting subjects aged 21--90 years using the described radioimmunoassays.

Prostaglandin biosynthesis by gastric mucosa. I. Studies in rat.

A technique for determination of the prostaglandin E2 biosynthetic capacity ( PGBC ) of gastric mucosa is described. The effects of food deprivation and indomethacin pretreatment on PGBC were studied. Indomethacin (1 mg/kg i.p.) significantly reduced the PGBC of fundal and antral tissue. This effect was more marked in the fundal tissue. Food deprivation for up to 22 h had no effect on fundal PGBC . In the antrum, a 12-hour fast caused a significant reduction in PGBC while a 22-hour fast had no effect. These changes in PGBC may relate to the increase in susceptibility to gastric ulceration caused by fasting or indomethacin pretreatment. This technique may be applicable to clinical studies.

Diabetic Chinese hamsters: metabolic effects of long term guar gum consumption.

The effect of 13 weeks of guar gum or cellulose diet consumption upon metabolic parameters was examined in diabetic and control adult Chinese hamsters. Diabetic hamsters displayed typical diabetic metabolic profiles. Both 8% guar gum and 8% cellulose diets maintained body weights in all 4 groups during the study. Diabetic and control hamsters fed guar gum drank less water as the study progressed. At weeks 9 and 13, diabetic hamsters fed guar gum excreted less urine compared to those fed cellulose. Diabetic hamsters fed guar gum had reduced urinary glucose excretion at weeks 1, 9 and 13 compared to those fed cellulose. Control hamsters fed either diet had normal urine volumes with only traces of glucose. Similar fasting plasma glucose levels were measured initially for all diabetic hamsters; all 3 subsequent measurements revealed lower levels for the group fed guar gum. Control hamsters had normal fasting plasma glucose levels. Comparable fasting plasma insulin levels were measured for all diabetic hamsters; these levels increased during the study. Control hamster fasting plasma insulin levels were 3 times higher and did not change. Throughout the study, diabetic hamsters fed guar gum consistently had healthier metabolic profiles than those fed cellulose.

Guar by-product improves carbohydrate tolerance in healthy human subjects.

Guar gum possesses distinct hypoglycemic properties. The other fraction of the guar bean, guar by-product (GBP), was studied to determine if it possesses any hypoglycemic properties. When 25 g GBP or wheat bran were consumed with a carbohydrate test meal by 10 healthy subjects, at 15 and 30 min after the GBP test meal significantly lower normalized plasma glucose responses were measured. Postprandial plasma insulin responses were similar after both test meals. During the first 60 min postprandially, the mean integrated plasma glucose response area was significantly lower after the GBP test meal. These data indicate that GBP, like guar gum, possesses hypoglycemic properties; because of the different chemical characteristics of these 2 guar bean fractions, it seems that their hypoglycemic properties are due probably to different mechanisms.

Bombesin-like immunoreactivity in developing human lung.

Bombesin-like immunoreactivity (BLI) was detected by a specific radioimmunoassay in extracts of 15 human lungs from fetuses, neonates, infants and children. A higher concentration of lung BLI was found in the fetal/neonatal group (2053.2 +/- 316.3 ng bombesin/g protein, n = 6) compared to the infant/children group (416.3 +/- 64.3 ng/g, n = 9). The peaking of BLI in lungs during the fetal/neonatal period suggests an important function for this peptide in intrauterine life and neonatal adaptation.

Metabolic responses to enteral and parenteral nutrition.

Seven pairs of rats were simultaneously infused with a chemically formulated nutritionally complete amino acid-glucose diet which was delivered, at the same rate, into a central vein or into a feeding gastrostomy. The intragastrically infused rats showed greater weight gain than did the intravenously infused rats. This could not be explained by fluid retention since intake and output were similar in the two groups of animals. There was a greater increase in serum immunoreactive insulin (IRI) at day 8 in the intragastrically infused animals, but a smaller increment in serum immunoreactive pancreatic glucagon (IRG) at that point. Levels of enteroglucagon or glucagon-like immunoreactivity (GLI) were maintained in the intragastrically infused rats but declined markedly in the intravenously infused rats. It is possible that the greater release of IRI seen with the intragastric amino acid-glucose feeding contributes to better disposal of nutrients and greater weight gain. The presence of nutrients in the intestinal lumen may have stimulated the release of GLI, which in turn is insulinotropic.

Extraordinary hyperbilirubinemia in a neonate with idiopathic hypertrophic pyloric stenosis.

This case describes an extraordinarily elevated total bilirubin level that reverted to normal 9 1/2 wk after Fredet-Ramstedt pyloromyotomy. Although the etiology of jaundice occurring in patients with IHPS remains uncertain, theories implicating inhibition of the glucuronyl transferase system have been proposed. Infants with IHPS have a documented hypergastrinemia. An hypothesis is offered, illustrated by this case, to explain the inhibition of the glucuronyl transferase system with resultant hyperbilirubinemia by the hypergastrinemia of idiopathic hypertrophic pyloric stenosis.

The gastrointestinal endocrine system.

Gastrointestinal endocrinology is the study of the hormonal regulation of digestion. A number of characterized polypeptide hormones have been localized in specific gastroenteropancreatic endocrine cells. The fact that some of these hormones are also found in nerve and brain cells has given rise to the concept of a gut-brain axis. The functional capacities of these endocrine cells are determined by their anatomic location; the luminal exposure of gastroenteric endocrine cells represents an additional avenue for stimulation and release that is not open to pancreatic endocrine cells. Gastroenteropancreatic hormones regulate carbohydrate metabolism, gastric acid secretion, pancreatic exocrine and gallbladder function, gastrointestinal motility and blood flow. These important regulatory hormones may in turn be controlled by a series of gastroduodenal releasing hormones.Diabetes mellitus is the most important metabolic disorder related to a gastroenteropancreatic hormone imbalance. Most tumours producing these hormones are of pancreatic origin and produce a number of hormones; insulinomas and gastrinomas are detected readily because of the serious metabolic distrubances they cause. Other instances of altered circulating concentrations of these hormones result from rather than cause the disease.The challenge of future study is to determine if postprandial changes in the plasma concentrations of these hormones are sufficient or necessary, or both, for the control of digestion.

Regulatory peptides of the gut and brain.

The concept of the gut-brain axis has emerged from the recent demonstration, mainly by radioimmunoassay and immunohistochemistry, that many peptides are common to both gut and brain cells. The general term regulatory peptide is at present the most appropriate for these peptides until more is known about their precise hormonal, neurotransmitter and neuromodulator activities. Consideration of possible local endocrine (paracrine) and neuroendocrine secretion necessitates re-evaluation of the importance of peripheral regulatory peptide concentrations. Central and peripheral administration of these peptides is a useful way to establish their potential regulatory roles in endocrine and nervous pathways. The concept of the gut-brain axis demonstrates the intimate relations between endocrinology and neuroendocrinology.

Chronic mild restraint protects the rat gastric mucosa from injury by ethanol or cold restraint.

The effects of chronic mild restraint on the susceptibility of the rat gastric mucosa to ethanol or cold-restraint injury were studied. Gastric mucosas of animals subjected to chronic mild restraint exhibited less damage when bathed with 40% ethanol than those of control animals. This reduced damage was observed with 2 days of mild restraint and was maximal (93% less damage; p less than 0.0005) when the animal was mildly restrained for 10 days. Pretreatment with indomethacin abolished the protection afforded by chronic mild restraint, suggesting a mechanism involving endogenous prostaglandin synthesis. Chronic mild restraint significantly (p less than 0.05) reduced the injury to the gastric mucosa caused by cold-restraint stress. This model of mild restraint may prove useful in future studies on the mechanism of stress-induced and other gastric mucosal lesions.

The antral gastrin-producing G-cell: biochemical and ultrastructural responses to feeding.

The effect of feeding on serum and antral immunoreactive gastrin (IRG) concentrations and on the ultrastructural appearance of antral G-cell granules has been examined. Serum and tissue IRG concentrations were dependent upon the length of time (12 or 48 h) the rats had been fasted before receiving food; IRG release was biphasic; the first peak was more pronounced in rats fasted 12 h. Antral tissue IRG content increased significantly postprandially. An initial depletion of antral IRG was seen in rats fasted 48 h. Examination of the subcellular distribution of antral IRG revealed more of the 5-15 min postprandal total IRG in the cytoplasm and less in the secretory granules. Ultrastructurally, G-cells from fasting rats contained mainly electron-dense granules. Five minutes postprandially numerous electron-lucent granules were observed. More electron dense granules were apparent 60 and 120 min postprandially. Fasting rats had the highest G-cell granule density index; a significantly lower index was observed 5 min postprandially. Indices at 60 and 120 min postprandially increased but were still lower than the fasting index. These studies indicate that gastrin biosynthesis is necessary for food stimulated gastrin release and that the electron density of the G-cells granules is not an accurate reflection of the G-cell gastrin content.

Human pancreatic polypeptide: studies of fasting and postprandial plasma concentrations.

Circulating human pancreatic polypeptide (HPP) was studied in 16 human subjects during two 24-h test periods, one fasting and another eating meals at 0830, 1230, and 1730. In six subjects the tests were repeated with propantheline administration. Blood was sampled every 30 min; additional blood samples were drawn 15 and 45 min postprandially. Mean HPP concentrations increased gradually during the day in 13 out of 16 fasting subjects, reaching an average peak at 2100. By 0200 mean HPP concentrations returned to initial fasting concentration. Propantheline eliminated this circadian rhythm. Biphasic plasma HPP responses were recorded after each of the three meals during the test. Calculation of integrated HPP outputs revealed similar outputs to the three meals; the percentage contribution of the first release phase increased with successive meals. Propantheline caused a 60% decrease in integrated HPP outputs. The first release phase was practically absent after the 0830 meal; however, distinct biphasic responses were present after the 1230 and 1730 meals. These studies demonstrate that fasting plasma HPP displays a cholinergic-dependent circadian rhythm, that postprandial plasma HPP responses are quantitatively similar throughout the day, and that different cholinergic activities are involved in the maintenance of these fasting and postprandial plasma HPP patterns.

Mucosal gastrin concentration, molecular forms of gastrin, number and ultrastructure of G-cells in patients with duodenal ulcer.

The mean antral immunoreactive gastrin (IRG) concentration of 38 duodenal ulcer (DU) patients was significantly higher (35-9+/-5-2 mug/g) than that of 21 controls (15-9+/-2-6 mug/g). Also the mean IRG concentration in the proximal duodenal mucosa of 15 DU patients (3-2+/-0-8 mug/g) was higher (but not significantly) than that of 10 controls (1-8+/-0-5 mug/g). The number of G-cells in the antral mucosa of 58 DU patients and in the duodenal mucosa of 29 DU patients was not larger than that of controls. The distribution of immunoreactivity in gastrin components has been investigated in the antral and duodenal mucosa of six DU patients and six controls. In the antral mucosa the mean percentage of G-17 was 93-3% in DU patients and 92-0% in controls. G-34 amounted to 4-0% in DU patients and to 5-0% in controls. The G-34 percentage in the duodenal mucosa was higher (however not significantly) in the DU patients than in the controls (50-1% versus 35-8%). Ultrastructurally, the antral G-cells of DU patients had a significantly lower density index of their secretory granules suggesting higher functional activity. It is concluded that the exaggerated serum IRG response of DU patients to different stimuli is not a consequence of an increased G-cell mass.