R. Arnold

Biochemical and morphological investigations of 30 human insulinomas

SummaryThirty 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.

Somatostatin and insulin release from isolated rat pancreatic islets stimulated by glucose

Somatostatin inhibits insulin release in vivo [l-5 J and in vitro [6-lo] after exogenous administration. This inhibitory action was discovered at a time when only the hypothalamus and some extrahypothalamic areas in the central nervous system were known to contain somatostatin-producing cells [ 1 l-l 21. The suggestion that somatostatin might be of physiological importance in the regulation of insulin secretion was, therefore, based on the assumption that somatostatin is released into the peripheral circulation and transported to the B-cell membrane at concentrations high enough to block secretion of insulin. The discovery that the D-cells of the islets of Langerhans react with antisomatostatin serum suggested local effects of the polypeptide via paracrine secretion. Somatostatin may indeed play a physiological role in the release of insulin [ 13171. We now present evidence that somatostatin is released from isolated rat pancreatic islets and that insulin and somatostatin release are interrelated.

Differential effects of atropine and a cholecystokinin receptor antagonist on pancreatic secretion

The present study evaluates the effect of atropine and of the cholecystokinin receptor antagonist loxiglumide on feedback regulation of basal pancreatic secretion in 6 healthy volunteers. The intraduodenal instillation of the protease inhibitor camostate reduced enzymatic activities of trypsin and chymotrypsin by 80%. This was accompanied by a strong increase in amylase and lipase output. The intravenous infusion of atropine (5 micrograms/kg.h) completely abolished the stimulatory effect of camostate on enzyme output. The infusion of loxiglumide (10 mg/kg.h) caused no changes in camostate-induced stimulation of enzyme output. Plasma levels of cholecystokinin were not altered after intraduodenal instillation of camostate whether atropine, loxiglumide, or saline were infused. We suggest that the protease inhibitor camostate, by inhibition of the enzymatic activity of trypsin and chymotrypsin, interferes with feedback regulation of basal pancreatic secretion in humans, and this mechanism is predominantly mediated by the cholinergic system.

Gastric inhibitory polypeptide (GIP), gastrin and insulin: Response to test meal in coeliac disease and after duodeno-pancreatectomy

SummaryThe response of serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG) and insulin (IRI) to a mixed standard meal was measured in 15 controls, 6 patients with coeliac disease, 26 patients with chronic pancreatitis and 6 patients with chronic pancreatitis and partial duodenopancreatectomy (Whipples procedure). Serum levels of IR-GIP, IRG and IRI were significantly reduced in patients with coeliac disease. The serum glucose increase was significantly smaller only during the first hour after the meal. Since small intestinal GIP- and G-cells are situated mainly in the glands of duodenal and jejunal mucosa their absolute number is not significantly reduced in coeliac disease. It is suggested that the release of IR-GIP and duodenal IRG is influenced by the rate of absorption of nutrients. In patients with chronic pancreatitis the IR-GIP release is significantly greater than in controls, the IRG release normal and the IRI response delayed. After Whipples procedure the IR-GIP response is increased significantly while the IRG secretion is abolished. This demonstrates that the duodenum is not necessary for GIP release and that pancreatic and jejunal gastrin are without clinical significance.

Trypsin Radioimmunoassay in the Diagnosis of Chronic Pancreatitis

Serum immunoreactive trypsin (IRT) determination has been recommended as a screening test in chronic pancreatitis. Using a commercial radioimmunoassay kit (RIA--gnost Trypsin; Behring-Werke, Marburg/Lahn, FRG) the interassay coefficient of variation was 26--44% for three different test sera. Gel filtration chromatography profiles revealed immunoreactivity in the position of 125I-trypsin and (less than 50%) in the void volume. The test was evaluated in controls (n = 90), chronic relapsing pancreatitis (CRP;n = 60) and after total pancreatectomy (n = 5). In 65% of the CRP cases decreased IRT values were found, whereas during acute attacks of CRP supranormal and normal values were found. After total pancreatectomy IRT levels were undetectable. It is concluded that the sensitivity of this IRT test is limited and that the available test system needs improvement.

Somatostatin and insulin release from isolated rat pancreatic islets in response to D-glucose, L-leucine, α-ketoisocaproic acid or D-glyceraldehyde: Evidence for a regulatory role of adenosine-3′,5′-cyclic monophosphate

Abstract Somatostatin and insulin release from isolated rat pancreatic islets was stimulated by glucose, leucine or α-ketoisocaproic acid. D-glyceraldehyde stimulated insulin release but diminished the secretion of somatostatin. Glucagon and theophylline amplified the glucose-induced somatostatin release. A regulatory role of the D-cells adenylate cyclase/phosphodiesterase system for the release of somatostatin is suggested. Furthermore, stimulation as well as inhibition of somatostatin release might be of significance for the secretory function of the B-cell.

Do Bile Acids Exert a Negative Feedback Control of Cholecystokinin Release

The influence of intraduodenal bile deficiency due to chronic bile duct obstruction and acute exogenous administration of bile acids on plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) was investigated. Fourteen patients with tumor-induced bile duct stenosis and five healthy volunteers were given a liquid test meal. Four of the patients had a simultaneous pancreatic duct stenosis. On another day 4 g chenodeoxycholic acid were administered concomitantly with the liquid test meal in six of the patients and all controls. Basal and meal-stimulated plasma CCK did not differ between patients and controls. A pancreatic duct stenosis, which was associated with diminished plasma PP concentrations, had no influence on plasma CCK release. Exogenous bile acids significantly reduced the postprandial CCK response in both groups. Bile-induced inhibition was significantly greater in patients than in controls (75 +/- 7% and 44 +/- 11%, respectively; p less than 0.05). It is concluded that intraduodenal bile is an important modulator of the postprandial secretory activity of the CCK cell. Although chronic intraduodenal bile acid reduction in tumor-induced biliary duct stenosis did not influence plasma CCK levels, a negative feedback control of plasma CCK by acute bile acid administration could be demonstrated.

Appearance of gastrin and somatostatin in the human fetal stomach, duodenum and pancreas.

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.

Response of gastric inhibitory polypeptide (GIF) to test meal in chronic pancreatitis — Relationship to endocrine and exocrine insufficiency

SummaryTwenty-nine patients with chronic pancreatitis had a significantly greater IR-GIP response to a test meal than 15 controls. This increased response was not related to the degree of steatorrhoea or glucose intolerance. It was most marked in a group of patients with moderately impaired IRI release and medium steatorrhoea. From this is concluded that the IR-GIP response to a test meal is determined by at least two factors: 1. feedback control via insulin secretion, 2. assimilation of fat. In chronic pancreatitis endocrine insufficiency may induce an exaggerated GIP response and severe exocrine insufficiency may prevent fat induced GIP release. Gastrin is not involved in the different GIP response in patients with chronic pancreatitis.

Serum gastric inhibitory polypeptide (GIP) in duodenal ulcer disease: relationship to glucose tolerance, insulin, and gastrin release.

Serum immunoreactive gastric inhibitory polypeptide (IR-GIP), gastrin (IRG), and insulin (IRI) were estimated in 41 normal weight patients with duodenal ulcer (DU) and 25 age-matched controls in response to a high calorie liquid test meal. 28 out of 41 DU patients had a hyperglycaemic glucose response during the test meal, and 15 had a pathological oral glucose tolerance test. Fasting and food-stimulated IR-GIP and IRG levels were significantly elevated in the DU patients. Serum IRI also increased to significantly higher levels in DU patients after the test meal. The degree of the greater hormone response was dependent on the glucose increase after the test meal in the case of insulin and GIP, but not in the case of gastrin. It is concluded: firstly, that a faster glucose absorption (possibly due to rapid initial gastric emptying or increased intestinal motility) is responsible for the high and short-lasting glucose peak and the increased GIP and insulin secretion; secondly, that the GIP response could well be causally related to the insulin response; thirdly, that hyposcretion of GIP is ruled out as a possible factor in the pathogenesis of gastric acid hypersecretion of duodenal ulcer patients.