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Bei 17 Patienten mit Ulcus duodeni wurde der Einflus der selektiven proximalen Vagotomie (SpV), in 12 Fallen kombiniert mit Pyloroplastik, auf die basale und postprandiale Gastrinfreisetzung untersucht. Dabei ergab sich ein Anstieg der Nuchterngastrinspiegel bei allen Patienten nach SpV. Dieser Anstieg des basalen Gastrinwertes war bei Patienten mit negativem postoperativem Insulintest hoher als bei insulin-positiven Fallen.

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.

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.

The influence of low and high fibre diets upon carbohydrate tolerance was examined in five maturity-onset, non-insulin dependent diabetics. After 14 days on a diet rich in natural fibre (30 g/day), the subjects consumed a high fibre (13 g) test meal. They then ate a low fibre diet (10 g/day) followed by a low fibre (1 g) test meal. Mean basal plasma glucose concentrations were similar after both fibre diets; however, both mean basal plasma insulin and gastric inhibitory polypeptide (GIP) were significantly lower after the high fibre diet. After the high fibre test meal, significantly lower mean plasma glucose, insulin and GIP concentrations were measured. This study is the first study to demonstrate the ability of an institutionally supervised diet of natural foodstuffs rich in fibre to improve carbohydrate tolerance in maturity-onset, non-insulin dependent diabetics. This findings is relevant to the dietary management of diabetics.

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.

1. Enzymes were detected in the smallest fetuses (8·5 cm). Generally, in the fetal samples, α-amylase and chymotrypsin activities were low, trypsin, phospholipase A and leucine amino peptidase showed a gradual increase and lipase remained nearly constant over the gestation period. 2. Enzyme activities of 12-week-old calves were higher than the fetal ones. 3. Sixteen-week-old calf activities (except lipase) showed a decrease approaching the lower adult levels. 4. Ultrastructurally, the smallest fetuses (< 19 cm) contained zymogen granules of a wide variety of shapes and sizes, scarce profiles of rough endoplasmic r reticulum and free ribosomes. 5. In larger fetuses, a more homogeneous population of zymogen granules was present with a progressively more organized cytoplasm with prominent rough endoplasmic reticulum. Sixteen-week-old calf and adult samples showed highly organized cytoplasm in a very active state. 6. These biochemical and ultrastructural results reflect the nutritional environment of the animals.

Summary. Human insulinoma tissue excised from seven patients was incubated with glucose (3.0 mg/ml) and 3H-leucine (100 μCi/ml) for a 15 min. pulse period. One third of the tissue was homogenized immediately in 0.3 M sucrose (pH 6.0), one third was homogenized after a 20 min. chase (with L-leueine 37S μg/ml) and the remaining third after an 80 min. chase. Subcellular fractions (cell debris, mitochondria, secretory granules, microsomes and S-100) were prepared by centrifugation. Their identity was confirmed by ultrastructural examination. Since only tumours revealing typical β-granules were investigated the secretory granule fractions contained the same types of granules as found in the normal human B-cell.—The S-100 contained approximately 40% of the immuno-reactive insulin (IRI). The secretory granule samples from five tumours were fractionated by sucrose gradient ultracentrifugation. At the three time intervals examined, a peak of radioactivity and IRI was located at 1.60 M sucrose in three of the tumours. The different granule types were not separable in the sucrose gradients. Endogenous proinsulin-like components (proinsulin) and insulin were released throughout the incubation. During incubation of tumour tissue the ratio of IRI release to content was significantly higher than that from isolated human pancreatic islets. Newly synthesized proinsulin was detected in the medium after the 15 min. pulse in five of the tumours; radioactive proinsulin and insulin were present in all the media after the 20 and 80 min. chase periods. Islets isolated from the pancreatic tissue of two insulinoma patients showed a much slower proinsulin and insulin turnover.—These data support the conjecture that human insulinomas have a more rapid turnover of proinsulin and insulin than normal pancreatic islet tissue, apparently as the consequence of defective IRI storage and release mechanisms.

Thirty human insulinomas have been investigated histologically and their immunoreactive insulin (IRI) content estimated. In most cases immunohistological and ultrastructural studies were also performed and the percentage of proinsulin-like components (PLC) in the tumour determined. Except for 1 case the IRI concentration in the tumours was lower (0.01–89.0 U/g) than in the islet tissue. Histologically, immunohistologically and ultrastructurally a variable number of tumour cells contained few and often no beta-granules, indicating a decreased storage capacity for insulin. This defective storage capacity seems to be the major functional abnormality of insulinoma cells. Ultrastructurally four types of insulinoma can be distinguished. The ultra-structural diagnosis of an insulinoma can only be made in type I (typical beta-granules, 13 cases) and type II (typical and atypical granules, 7 cases) but not in type III (atypical granules only, 4 cases) and type IV (virtually agranular, 4 cases). The type IV tumours had the lowest IRI concentration and did not respond to diazoxide treatment. The IRI concentration of the uninvolved pancreas of 19 patients was 2.0±0.2 U/g and in the range of non-diabetic adults. — The percentage PLC in 19 insulinomas was higher (5.3–22%) than in the pancreas of human adults with and without insulinoma (1.7–4.8%). The percentage of PLC in the serum of patients with insulinoma was always higher than in their tumours (33–61%). It is suggested that the higher PLC levels found in the tumour and serum of insulinoma patients are the consequence of the reduced storage capacity of the tumour cells resulting in a rapid passage through the granular route or even a non-granular release of newly synthesized insulin.

The gastroplasty tube has been used in the control of reflux since it was originally described by Collis in 1961. Several variations of the procedure have been reported indicating a low frequency of anatomic recurrence but a high frequency of reflux. Two forms of gastroplasty procedure are used: partial fundoplication in which gastric fundus incompletely wraps the gastroplasty and high pressure zone, and total fundoplication in which a circumferential wrap is constructed. The authors conducted a clinical review, using the patient's history, radiology and manometry, of 135 patients with partial fundoplication gastroplasty (PFG) and 250 patients with total fundoplication gastroplasty (TFG). In both groups the anatomic recurrence rate was low; however, with PFG the frequency of reflux was 44.6% and 25.7% of patients had notable symptoms. With TFG no patient had reflux. The response of the gastroplasty tube to meal-induced gastrin release and to neurogenic stimulation was tested. Basal tube pressure was low and showed no response to gastrin release and no augmented neurogenic response. It was concluded that the gastroplasty tube did not have intrinsic properties of value in controlling reflux and that reflux control depended upon the method of fundoplication. The role of the gastroplasty tube is in preventing anatomic recurrence.

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 relationship between arterial blood pressure and clinically apparent diabetes mellitus was examined by measuring blood pressure, under standardised conditions, in 735 ambulant diabetic patients attending St. Mary's and King's College Hospital, London. Other biometric, clinical and family data were also systematically collected. A large proportion of first degree relatives of the diabetics and a control group of first degree relatives of non-diabetics were also seen and examined; they were also tested for the presence of unsuspected diabetes. Blood pressure in diabetics was evaluated in two ways. Mean pressures (systolic and diastolic) were calculated by age and sex and compared with similar data from two British non-diabetic populations. In addition, age and sex adjusted blood pressure "scores" were derived for each of the diabetic propositi and for the relatives by calculating the degree to which their pressures deviated from the mean of a corresponding age/sex group of non-diabetics. These deviations were then made comparable by standardising them for the systematic change in variance with age and sex. Using both "raw pressures" and "adjusted scores" the influence of age, sex, obesity, arm girth, response to diagnosis and ethnic, obstetric and anamnestic features were examined. Analysis of the influence of various characteristics of the diabetic state on blood pressure was made; this included mode of presentation, known duration; insulin dose and degree of metabolic control. Finally the relationship of blood pressure levels to the long-term sequels of diabetes was analysed with special reference to renal disease, eye changes, neuropathy and arterial disease. No systematic difference between arterial blood pressure in diabetics and a suitable control population was detected. Younger patients, females more than males, tended to have somewhat higher mean diastolic pressures but these were balanced by rather lower mean pressures in older diabetics. There was evidence of raised pressure levels at the time of diagnosis of diabetes, particularly in older patients, which "settled" with time for reasons which were not clear. The relationship of arterial pressure with adiposity was comparable to that in non-diabetics. After allowance for age and sex, blood pressures and scores were not related to the mode of onset of the diabetes. In the youngest onset group, however, known duration of diabetes appeared to correlate positively with arterial pressure in excess of the effect of age. Insulin dose and metabolic characteristics of the diabetes showed little clear association with arterial pressure but, as expected, patients with evidence of renal disease had higher mean pressures. However, cause-effect relationship between raised pressure and renal disease in diabetics may operate in both directions. Some elements of retinopathy were positively correlated with blood pressure; others were not. The role of co-existing renal disease in determining this association was examined...

The effect of selective proximal vagotomy (SpV) with (12 cases) and without (5 cases) pyloroplasty upon basal and food stimulated serum immunoreactive gastrin (IRG) was studied in duodenal ulcer patients. Following SpV, fasting serum IRG increased in all subjects; the increase was more pronounced in subjects whose postoperative insulin tests were negative. Postoperatively, the mean integrated IRG output over 2 hrs in response to a meal was significantly higher than the preoperative mean value in the 17 patients. Pyloroplasty had no effect upon the IRG response following a test meal.

The serum immunoreactive gastrin (IRG) level in infants with confirmed idiopathic hypertrophic pyloric stenosis (IHPS) has been determined and compared to that found in vomiting infants without IHPS, in normal infants, and in normal adults. The mean serum IRG level of normal infants (103 +/- 9 pg/ml (mean +/- SEM) exceeded that of normal adults (28 +/- 5 pg/ml). The preoperative mean serum IRG level in IHPS infants (256 +/- 26 pg/ml) was significantly higher than that of both normal infants and vomiting infants without IHPS (93 +/- 9 pg/ml). Twenty-five per cent (5/20) of the IHPS infants had serum IRG levels within the upper range of normal infants. Fasting serum IRG levels in IHPS infants were not altered immediately by pyloromyotomy. The results from this study suggest a relationship between gastrin and idiopathic hypertrophic pyloric stenosis.

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.

The gestational time of appearance of gastrin and somatostatin in the human fetal stomach, duodenum and pancreas was examined. Immunoreactive gastrin (IRG) is detected in antral, duodenal and pancreatic extracts of a 7.0-cm (crown-heel length) fetus. More IRG is extracted from the duodenum than the antrum. Duodenal IRG concentration from fetuses of 16.0--26.0 cm are higher than younger fetal and adult concentrations. Antral IRG concentrations are one tenth of the adult contents. Very small IRG concentrations are present in the human fetal pancreas. Gastrin immunohistochemical staining is positive first in duodenal (6.5-cm fetus) and later in antral (12.5-cm fetus) mucosa; pancreatic tissue is negative for gastrin immunohistochemistry. Type IV cells are encountered in antral and duodenal mucosa of 4.0-cm fetuses; other endocrine cells appear with fetal growth. Not until much later in gestation (21.0 cm) do typical G cells appear. These results suggest that early in fetal life gastrin is produced by the type IV cell. Somatostatin immunohistochemical staining is positive in stomach, duodenum and pancreas in 6.5-cm fetuses. Immature D cells are found in antral and duodenal mucosa of 5.0-cm fetuses and mature D cells in 11.0-cm fetuses.

Forty human insulin-producing tumors were investigated with histochemical, immunohistological and ultrastructural methods and extracted for insulin and proinsulin. These studies resulted in the following findings: 1) A variable number of tumor cells contained only a few or often no beta granules. 2) The insulin concentration was lower and the proinsulin percentage higher in insulinoma cells compared with normal beta-cells. 3) According to the ultrastructural appearance of the secretory granules four types of insulinoma were established. 4) Insulinomas frequently contained cells with atypical secretory granules which were Grimelius silver-positive. Their similarity to the Type IV islet cell and to cells regularly found in gastrinomas, Verner-Morrison tumors and glucagonomas suggests that all endocrine pancreatic tumors originate from a common precursor cell. 5) The morphological and biochemical findings support the theory that uncontrolled hormone release and/or decreased storage capacity are responsible for fasting hyperinsulinism in insulinoma patients. 6) The severity of hypoglycemia symptoms and the result of stimulatory tests were not related to the size, the insulin concentration and the total insulin content of the tumor.

The rate of proinsulin/insulin turnover has been studied in human insulinoma tissue from ten patients. During the incubation of tumor tissue the ratio of immunoreactive insulin (IRI) release to content was significantly higher than that from isolated human pancreatic islets. The tumor cell cytoplasm (100,000 g supernatant S-100) contained approximately 45% of the IRI. Endogenous proinsulin and insulin were released throughout the incubation. Newly synthesized proinsulin was detected in the 15 min pulse microsomal, secretory granule, S-100 and media samples. These results suggest that defective hormonal storage and release mechanisms are operative in human insulinoma cells resulting in a higher turnover of proinsulin and insulin compared with pancreatic islet tissue.

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.

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.

The effects of sustained fiber ingestion on gastric emptying glucose tolerance, hormone responses, and jejunal absorption of glucose and lysine were studied in healthy volunteers. Subjects were placed on a low-fiber (3 g) diet for 2 wk, followed by 4 wk of an isocaloric diet supplemented with 20 g/day of either apple pectin (7 subjects) or alpha-cellulose (6 subjects). At the conclusion of each dietary period subjects ingested a low-fiber breakfast surface-labeled with 99mtechnetium sulfur-colloid. Gastric emptying half-time, plasma glucose, calcium, phosphorus, insulin, glucagon, gastrin, human pancreatic polypeptide, and motilin were determined. Gastric emptying half-time was prolonged approximately twofold after pectin supplementation (p less than 0.005) and returned to normal 3 wk after discontinuing pectin supplementation. Cellulose supplementation did not alter the gastric emptying rate. Plasma glucose, calcium, phosphorus, and hormonal responses to the meal were unchanged after either pectin or cellulose supplementation. Pectin ingestion did not impair intestinal absorption of glucose or lysine. In contrast to sustained cellulose ingestion, sustained pectin ingestion slows the gastric emptying rate; the mechanism underlying this adaptive effect is unknown.

By immunohistochemistry, bombesin, calcitonin and leu-enkephalin was localized in endocrine cells of human lungs from various age groups. It is suggested that at least 3 different peptide containing endocrine cells may be present in human lung.

Immunoreactive gastrin (IRG) is found in both tissues and blood. Gastrin was isolated as a polypeptide of seventeen amino acids (G-17) which is present in two forms designated gastrin I and gastrin.II. Gastrin II contains a sulphate group on the tyrosine residue at position 12; gastrin I is sulphate-free. Studies in recent years have established the heterogeneity of IRG in both tissue and blood [1, 2].

Fur die vermehrte Saurebildung bei Patienten mit Ulcera duodeni (U. d.) ist nach den Untersuchungen Dragstedts nicht eine Uberproduktion des antralen Hormons Gastrin, sondern eine gesteigerte Aktivitat des Vagus verantwortlich [1]. Diese Untersuchungen, die noch aus einer Zeit stammen, in der kein Radio-immunoassay fur Gastrin zur Verfugung stand, bilden die Grundlage fur die heute allgemein akzeptierten chirurgischen Verfahren der Vagotomie bei Patienten mit U. d. [2]. Es gibt jedoch Hinweise dafur, das auch das antrale Hormon Gastrin fur die vermehrte Saureproduktion von Patienten mit U. d. mitverantwortlich ist. So liegt die Dosis Pentagastrin, die erforderlich ist, um eine halbmaximale Stimula­tion der Parietalzellen zu erreichen, bei Patienten mit U. d. niedriger als bei magengesunden Kontrollpersonen [3]. Auch die stark reduzierte Sauresekretion antrektomierter U. d.-Patienten wahrend einer vagalen Stimulation spricht da­fur, das das Gastrin fur eine regelrechte Funktion der Parietalzellen mitverant­wortlich ist [4].

Suggestions that diabetes of younger- and older-onset are inherited differently have been examined in a family study which compares the first-degree relatives of 735 diabetic patients with those of 514 ‘control’ patients. Verbally reported histories from the propositi indicated an excess prevalence of known diabetes among the siblings of younger-onset diabetics; however, when the ostensibly normal, first-degree relatives were examined a high frequency of unsuspected glucose tolerance test abnormality was found. When the diabetes prevalence in relatives of diabetics was compared with that in relatives of controls (K ratio), a method at present widely used to determine the mode of inheritance, a number of problems arose suggesting that this means of genetic analysis may be misleading in diseases such as diabetes. It is concluded, for reasons which are discussed, that differences in prevalence ratios cannot be accepted as good evidence for different modes of inheritance of younger- and older-onset diabetes in man.

It is proposed that a proinsulin-like molecule formed the ancestral protein from which insulin, glucagon, gastrin and secretin evolved by an evolutionary pathway involving codon frameshift mutation.