Jens F. Rehfeld

The Effect of Gastrin on Basal- and Glucose-Stimulated Insulin Secretion in Man

The effect of gastrin on basal- and glucose-stimulated insulin secretion was studied in 32 normal, young subjects. The concentration of gastrin and insulin in serum was measured radioimmunochemically. Maximal physiologic limit for the concentration of gastrin in serum was of the order of 160 pmol per liter as observed during a protein-rich meal. Oral ingestion of 50 g glucose produced a small gastrin response from 28+/-3 to 39+/-5 pmol per liter (mean +/-SEM, P < 0.01). Intravenous injection or prolonged infusion of gastrin increased the concentration of insulin in peripheral venous blood to a maximum within 2 min followed by a decline to basal levels after a further 10 min. The minimum dose required to induce a significant insulin response (31.2 ng gastrin per kg) increased the gastrin level in serum above the physiologic range. Maximum effect was obtained with 500 ng gastrin per kg. When 15.6 ng (7.1 pmol) gastrin per kg body weight and 25 g glucose were injected simultaneously, the glucose-induced insulin response was potentiated (from 2.32+/-0.33 to 4.33+/-0.98 nmol per liter per 20 min, P < 0.02), even though gastrin concentrations only increased to 71.2+/-6.6 pmol per liter. No effect, however, was noted on glucose disposal. 15.6 ng gastrin per kg given i.v. 30 min before an i.v. glucose tolerance test was without significant effect on the insulin response. The results indicate that gastrin can stimulate a rapid and short-lived release of insulin. In physiologic concentrations gastrin potentiates the glucose-stimulated insulin secretion and is without effect on basal insulin secretion. A small release of gastrin during oral glucose ingestion may to a limited extent contribute to the nonglycemic insulin secretion. During protein ingestion, gastrin probably stimulates insulin secretion significantly.

Three components of gastrin in human serum Gel filtration studies on the molecular size of immunoreactive serum gastrin

Abstract Sera obtained from 6 normal subjects during a protein-rich meal and sera from 16 subjects with hypergastrinaemia (pernicious anaemia) were subjected to gel filtration on Sephadex G-50 fine columns. The concentration of gastrin in the effluent was determined by a sensitive radioimmunoassay. Three components of gastrin were observed. (1) Component I with a Stokes radius of 2.27 ± 0.08 nm (mean ± S.D.) was eluted immediately prior to proinsulin. 18.4 ± 7.6% (mean ± S.D.) of the total immunoreactive gastrin was found in this component, and it was present in 19 of 22 sera. (2) Component II with a Stokes radius of 1.52 ± 0.04 nm was eluted corresponding to the “basic gastrin” of Yalow and Berson. It comprised 72.6 ± 11.5% of the immunoreactive gastrin. In one serum this second component could not be detected. (3) Component III was measured in the effluent eluted after insulin. It comprised on average 9.1% of the immunoreactivity, and was detectable in only half of the sera. The elution pattern of this component was less well defined, and did not allow calculation of a molecular size. Gel filtration of serum in human plasma at 37°C, incubation with 8 M urea, and incubation with 0.1 M dithiothreitol did not alter the distribution of the components. Incubation with trypsin converted the two big components to a heptadecapeptide-like gastrin component with a Stokes radius of 0.81 ± 0.05 nm. In calibration studies synthetic human heptadecapeptide gastrin was found to have a radius of 0.88 ± 0.08 nm. No relationship between cholecystokinin and the gastrin components could be demonstrated using three gastrin antisera with different specificity against cholecystokinin. The findings demonstrate that a significant fraction of immunoreactive gastrin in serum is present as a component with a molecular size greater than that of the two components described so far. It is suggested, that the poorly defined small component (III) represents decomposition fragments of the larger components (I and II).

Concentration and component pattern in gastric, duodenal, and jejunal mucosa of normal human subjects and patients with duodenal ulcer

The total concentration of gastrin and distribution of gastrin components were examined in mucosal biopsies from corpus, antrum, duodenum, and jejunum from normal subjects and patients with duodenal ulcer. The concentration was highest in the antrum, being 12.1 ± 1.9 nmol per g of mucosa (mean ± SEM) for normal subjects, and 9.0 ± 1.6 nmol per g of mucosa for duodenal ulcer patients (P = 0.03). A steep gradient was found distally: in the proximal duodenum the concentration was 0.1; in the distal duodenum, 0.02 to 0.01; and in the proximal jejunum, less than 0.01 of the antral concentration. In corpus of the stomach, the concentrations were similar to those found in the jejunum. Gel filtrations showed that most gastrin immunoreactivity was eluted in positions corresponding to serum component II (gastrin-34-like) and III (gastrin-17-like), but immunoreactivity corresponding to all the components present in serum was found. No interference from cholecystokinin was observed in duodenal biopsies. In corpus, antrum, and jejunum component III was the predominant form, whereas component II made up half of immunoreactive gastrin in the duodenum. No major differences were observed between normal subjects and duodenal ulcer patients. There was no simple relationship between acid secretion and mucosal gastrin concentration, but ulcer patients with the highest acid secretion had the lowest antral content and the highest duodenal content.

Distribution and properties of gastrin cells in the gastrointestinal tract of chicken.

SummaryIn the digestive tract of the chicken, numerous cells showing gastrin immuno-reactivity were found in a narrow zone joining the gizzard with the duodenum. Here the mucosa resembled that of the mammalian pyloric gland area (antrum). The gastrin cells, which were rarely seen outside this zone, stained argyrophil with the technique of Grimelius but not with that of Hellerström-Hellman. The latter technique instead demonstrated another large cell population that did not react with the Grimelius stain. Ultrastructurally, the mucosa was richly endowed with endocrine-like cells, the majority of which belonged to either of two cell populations. In accordance with the morphological findings, extracts from the narrow antrum-like zone were found to contain large amounts of gastrin-like immunoreactivity; only traces occurred in the remainder of the gut. Gel chromatography revealed that the dominating form of chicken gastrin was heptadecapeptide-like.

Effect of Metiamide, a Histamine H2-Receptor Antagonist, on Mucosal Blood Flow and Serum Gastrin Level

In dogs with gastric fistulae and vagally denervated Heidenhain pouches, metiamide, a histamine H2-receptor antagonist, infused intravenously in a dose of 12 μmoles per kg-hr, inhibited near maximal acid responses to histamine, pentagastrin, Urecholine, or a peptone meal. Atropine sulfate (0.12 μmole per kg-hr) did not significantly affect acid output induced by histamine, but was a more effective inhibitor of acid secretion stimulated by pentagastrin, Urecholine, or a peptone meal. Serum gastrin response to a peptone meal was unchanged by metiamide but partly suppressed by atropine. The inhibitory effect of metiamide was always associated with a marked reduction in mucosal blood flow. The ratio of aminopyrine concentration in the gastric juice and blood plasma was not significantly changed by metiamide, indicating that the persistent reduction in gastric mucosal blood flow was secondary to an inhibition of gastric secretion.

Treatment of Zollinger–Ellison Syndrome with Streptozotocin

ALTHOUGH streptozotocin has been used successfully in treatment of malignant insulinomas and carcinoid tumors of the gastrointestinal tract,1 gastrinomas have apparently not been treated with this ...

Simultaneous recording of the gastro-entero-pancreatic hormonal peptide response to food in man

The serum or plasma concentrations of gastrin, gastric inhibitory polypeptide (GIP), gut glucagon-like-immunoreactivity (gut GLI), secretin, vasoactive intestinal polypeptide (VIP), insulin, glucagon, and pancreatic polypeptide (PP) were recorded simultaneously following the ingestion of a normal, mixed meal in seven healthy, normal weight men. The concentrations of PP and gastrin increased within 10 min. Subsequently GIP, insulin, glucagon, and gut GLI increased in the order mentioned. The mean concentrations of secretin and VIP were not affected by the meal, athough transient decreases in secretion concentrations could be detected in all subjects. The concentrations of the other hormones remained elevated for 4 hr or more. Perhaps the period of observation following food stimulation of gastro-entero-pancreatic hormones should be extended.

The enteral insulin-stimulation after Whipple's operation.

SummaryThe insulin response to oral and intravenous glucose was measured in ten patients after resection of antrum, duodenum, proximal jejunum, and the head of pancreas (Whipples operation). Compared to matched normal subjects the operation reduced neither the total nor the gut hormone induced part of the insulin response to oral glucose. The results suggest, that hormones from the first part of the intestinal tract are not necessary as incretins.

Effect of jejunoileostomy on glucose and insulin metabolism in ten obese patients

Abstract Ten subjects underwent a jejunoileostomy in the treatment of obesity. The blood glucose and serum immunoreactive insulin response to oral and intravenous glucose was determined ten days before, and with varying intervals up to 18 months after the operation. The reduced intestinal glucose absorption was compensatorily improved without reaching the preoperative capacity. Fasting blood sugar levels tended to be low for a long time after the operation but rose later on. The intestinal insulinotropic action remained preserved. A generally improved glucose tolerance and normalization of hyperinsulinism was correlated to weight reduction. We conclude that none of the reported effects of jejunoileostomy on glucose and insulin metabolism contraindicate this surgical treatment of obesity.

Effect of Sulfation of CCK-8 on Its Stimulation of the Endocrine and Exocrine Secretion from the Isolated Perfused Porcine Pancreas

The secretory effect of sulfated and nonsulfated cholecystokinin octapeptide (CCK-8) was studied on the isolated perfused porcine pancreas. Both CCKs in concentrations from 10(-11) to 10(-8) mol/l in the presence of glucose (7.5, 5.0 or 3.5 mmol/l) were without effect on insulin and glucagon release. The exocrine secretion was stimulated by both CCKs in a dose-dependent manner, but sulfated CCK-8 was considerably more potent. The study shows that CCK-8, a major constituent of endogenous CCK, does not contribute to the incretin mechanism, irrespective of degree of sulfation. In contrast, CCK-8 is a potent stimulator of exocrine pancreatic secretion. For this effect sulfation is crucial.