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Gastrin and insulin levels following protein ingestion were measured in control subjects, in patients with vagotomy and pyloroplasty and in patients with vagotomy, antrectorny and gastroenterostomy. Peak gastrin levels preceded peak insulin levels, but no relationship between gastrin output and insulin output was found. The insulin response in patients with impaired gastrin release was similar to that seen in patients with normal gastrin release. Insulin levels after oral glucose in patients with malignant Zollinger-Ellison syndrome were similar to those in patients after gastrectomy, in spite of marked differences in gastrin level. These studies do not suggest that gastrin stimulates insulin release.

Serum gastrin responses to intravenous L-arginine hydrochloride were measured in insulinopenic and noninsulinopenic patients with chronic pancreatitis and in suitable control subjects. There were no differences between any of the groups studied. Pancreatitis did not impair gastrin responses to arginine nor was gastrin an important determinant of insulin secretion in these patients.

Sixteen patients (aged 3.5-14.3 years) with normal jejunal mucosa, originally diagnosed as having coeliac disease at least 18 months before, were started on gluten challenge. The 'end point' of challenge was significant deterioration in jejunal mucosa morphologically and morphometrically. Studies carried out both before and after challenge included intestinal absorption of D-xylose and glucose, and release of insulin and N-terminal glucagon-like immunoreactivity (N-GLI). After gluten challenge, there were significant increases in plasma N-GLI at both 45 (P less than 0.05) and 120 minutes (P less than 0.03) after oral glucose. Significant reduction occurred in glucose absorption at 45 minutes (P less than 0.04), in one-hour D-xylose absorption (P less than 0.01) and fasting serum cholesterol (P less than 0.01). Plasma N-GLI showed significant negative correlations with D-xylose absorption (P less than 0.003) and serum cholesterol (P less than 0.004).

Enteropancreatic polypeptide responses during a 50 g oral glucose tolerance test were studied in 10 young men, 10 young women, 10 elderly men and 10 elderly women. Elderly females had higher gastric inhibitory polypeptide (GIP) responses to oral glucose than elderly males. Elderly males and females had higher fasting and post-glucose human pancreatic polypeptide (HPP) levels than young males and females. N-Glucagon-like immunoreactivity (N-GLI) responses differed between the young and elderly. In the young, N-GLI levels fell after oral glucose but in the elderly they rose. Post-glucose C-glucagon-like immunoreactivity (C-GLI) responses were higher in elderly females than in young females. The significance of the higher plasma levels of GIP, N-GLI and C-GLI following oral glucose in elderly females compared to elderly males is unclear.

Pancreatic polypeptide (PP), a recently discovered pancreatic hormone, is potentially a marker for endocrine tumors. Consequently, we devised a radioimmunoassay for it, using antisera (raised in rabbits) to bovine PP, 125I-labeled bovine PP (purified by anion-exchange chromatography), and human PP standards. Concentrations circulating in fasting, normal subjects were measured. Statistical analysis of the results revealed a skewed distribution. An age-related increase was also observed. Evaluating PP concentrations in sera from 23 patients with endocrine tumors, we found increased values in a few cases of Zollinger-Ellison syndrome, medullary carcinoma of the thyroid, carcinoid syndrome, and one tumor producing vasoactive intestinal polypeptide (VIPoma). In contrast, values from five insulinomas and one glucagonoma were within the normal reference interval. Thus, an increased value for PP in a fasting individual may suggest the diagnosis of an endocrine tumor but is not a diagnostic prerequisite.

Gastric acid secretion, pepsin secretion, and fasting serum gastrin levels were measured in 23 patients with duodenal ulcer disease, divided into three groups which received either cimetidine 800 mg daily, cimetidine 1600 mg daily, or ranitidine hydrochloride 300 mg daily for eight weeks. Pentagastrin tests were carried out at intervals both before and after treatment. Each dose of cimetidine reduced acid secretion to 42% of control one week after starting therapy. Ranitidine reduced acid secretion to 33% of the pretreatment value. Acid secretion remained suppressed to these levels throughout treatment with each drug. Acid secretion returned to pretreatment levels in all patients one week after treatment and remained normal until the end of the study. Both drugs reduced pepsin, which fell to 64% and 61% (p less than 0.01) after 800 mg and 1600 mg cimetidine respectively and to 65% (p less than 0.005) with ranitidine after one week's treatment. Pepsin secretion remained at this reduced level in both cimetidine groups till the end of treatment. Pepsin levels fell to 50% at two weeks of therapy with ranitidine but stabilised at this level till the end of therapy. Cimetidine withdrawal was followed by a return towards pretreatment levels of pepsin secretion; but secretion remained significantly depressed (p less than 0.05) to the end of the study period. In the ranitidine-treated patients pepsin output returned to normal after drug withdrawal. Fasting gastrin levels rose during treatment with both drugs but failed to reach significant levels. After withdrawal of treatment fasting serum gastrin levels returned to normal in all three groups of patients.

1. Whole body glucose turnover and absorption of a 50 g glucose drink was studied in six healthy volunteers on two occasions, 4 h after a ‘breakfast’ of 50 g of glucose, mixed on one occasion with 20 g of guar gum. 2. Plasma glucose concentrations were significantly reduced with guar gum compared with those obtained without guar gum (P < 0.0001). 3. Whole body glucose turnover studied by an intravenous primed dose constant infusion technique using d-[3-3H]glucose showed no significant difference between the two groups: 353 ± 15 mmol with guar and 350 ± 9 mmol without guar. 4. Total oral glucose absorption, followed with a D-[1-14C]glucose tracer, was significantly decreased by guar treatment, being 219 ± 3 mmol with guar and 239 ± 5 mmol without guar (P < 0.05). 5. Serum insulin levels were lowered by guar treatment (P 6. Blood lactate concentrations were raised in the guar treated group (P < 0.05) whereas pyruvate, alanine, glycerol and 3-hydroxybutyrate concentrations did not differ significantly. 7. These results support the suggestion that guar improves second-meal tolerance to glucose by decreasing absorption.

Oral glucose tolerance tests were performed in young and elderly subjects with minimal risk factors for diabetes mellitus. Compared to the normal glucose tolerance in the young there was a 45% rate of impaired tolerance in the elderly. Fasting insulin levels were significantly lower in the elderly but post-glucose insulin responses in the first hour were similar in young and elderly subjects. Peripheral insulin action was assessed in terms of the 125 monoiodoinsulin binding to specific insulin receptor sites on circulating lymphocytes in the young, the elderly and a group of age and sex matched obese maturity-onset diabetics. Specific insulin binding was not significantly different in the elderly than in the young but was significantly lower in the diabetics than the young and the elderly. The results suggest that neither defective insulin binding are major causative factors in the reduced glucose tolerance of the elderly.

Pancreatic function was assessed prospectively in a group of 18 treated adult coeliac patients, most of whom were asymptomatic. The para-aminobenzoic acid (PABA) test indicated exocrine pancreatic insufficiency in three patients, all of whom had persisting gastrointestinal symptoms. Arginine, 5 g intravenously, was used to stimulate pancreatic islet cells; basal and stimulated concentrations of plasma insulin, C-terminal glucagon, N-terminal glucagon, and blood glucose did not differ from asymptomatic nondiabetic control subjects. After gluten withdrawal, coeliac patients who responded clinically had no evidence of significant pancreatic impairment, but consideration of exocrine pancreatic insufficiency is worthwhile in those patients with persisting symptoms.

Immunoreactive secretin (IRS) and immunoreactive insulin (IRI) levels were measured in humans and dogs following the intraduodenal instillation of hydrochloric acid. IRS levels rose after acid in both instances, but a concomitant rise in peripheral IRI levels was not noted. Premedication of the humans with Scopolamine prevented a rise of IRS in the human subjects. It is concluded that the endovenous release of IRS alone does not result in increased IRI levels in peripheral blood and that IRS release may be under vagal control.

Abnormal acid production or handling is thought to be involved in duodenal ulceration. Gastric emptying of 25 mmol hydrochloric acid (250 ml 0.1 M solution) was studied by using an isotopic method in control and ulcer subjects. Plasma gastrin and secretin levels were simultaneously measured. Gastric emptying was significantly faster in ulcer subjects using several parameters. Plasma gastrin levels were suppressed in both groups, with equivocal differences between them. Mean plasma secretin levels showed no significant elevation in controls and at only one point in ulcer subjects. Mean elevation in plasma secretin levels during intermediate phase of gastric emptying (T30-70) correlated with rate of acid loss from stomach in both groups. Regression lines were significantly different in position, however, and indicated a higher threshold for secretin release in ulcer subjects. The significance of this in the pathogenesis of duodenal ulcer is discussed.

Hypersecretion of gastric acid and accelerated intestinal transit are largely unexplained consequences of massive resection of the small bowel; several postulated humoral mechanisms remain unsubstantiated. The purpose of the study was to investigate the effects of 75% resection of the distal small bowel in dogs on circulating levels of a range of gastrointestinal hormones. Basal and meal-stimulated concentrations of insulin, secretin, gastrin, pancreatic glucagon, and total glucagon-like immunoreactivity (GLI) were measured by radioimmunoassay techniques. After resection, significant depletions of basal and stimulated total GLI (p less than 0.05 -- p less than 0.001) and a significant rise of stimulated gastrin (p less than 0.05) were discovered. These hormonal alterations may produce an important imbalance of humoral influences on gastrointestinal function. It is suggested that these changes may hold a key to the aetiology of the complications of massive resection of the small bowel.

The prevalence of gastrinomas and the Zollinger-Ellison syndrome is unknown. In order to examine a high risk group of patients, basal and secretin-provoked plasma gastrin levels were determined in 50 consecutive patients, predominantly from the west of Scotland. All had endoscopically proven recurrent peptic ulceration following duodenal ulcer surgery. This resulted in three cases strongly suspected of having a gastrinoma. Further investigations including exploratory laparotomy were unable to demonstrate a gastrinoma in two, but the evidence suggested an occult tumour in one. In this remaining unoperated patient, the serum gastrin returned to normal. The reference range for both basal and secretin stimulated gastrin response and percentage change has been determined in normal control subjects (n=10) and in primary ulcer patients (n=20). It is concluded that in this study, gastrinomas had a less than 2 per cent prevalence in patients presenting with recurrent peptic ulceration. As the diagnosis of a gastrinoma changes the surgical approach, conducting screening tests still seems warranted.

SUMMARY Carbohydrate metabolism has been investigated in eight patients with Klinefelter's syndrome. Seven of the eight had a normal oral glucose tolerance curve; one patient had slightly impaired tolerance. Plasma insulin levels were measured in response to the glucose load and were normal in six and slightly abnormal in two patients; one of the latter had an early increased and the other a delayed insulin response. No definite conclusions are reached regarding the possibility of a significant association between Klinefelter's syndrome and diabetes mellitus.

The ability of the liver to metabolise insulin in response to varying blood insulin levels was studied using normally fed, starved and streptozotocin diabetic rats. Insulin clearance by the livers of fasted and diabetic rats was significantly increased compared with normal fed controls. Administration of insulin to diabetic animals prior to liver perfusion, or an increase in the concentration of the hormone in the perfusion medium used for normal livers resulted in a significant decrease in clearance. The percentage uptake of insulin during single passage through the livers of starved and diabetic animals was significantly greater than normal.

SUMMARY An oral glucose tolerance test was performed in eight patients with gonadal dysgenesis and in two a diabetic response was found. The plasma insulin levels were estimated in response to the glucose load and were abnormal in five out of the six patients examined. The blood sugar response to the standard insulin tolerance test was normal in six patients and showed increased insulin sensitivity in two. Plasma cortisol concentration was measured in response to the hypoglycaemia induced by insulin and in seven out of the eight patients rose considerably indicating a normally functioning pituitary-adrenal system. The sera of all eight patients were examined for auto-antibodies and were essentially negative. Possible reasons for the abnormalities in carbohydrate metabolism are discussed and it is suggested that gonadal dysgenesis may predispose to diabetes.

Oral glucose tolerance tests were performed and plasma insulin levels measured by immunoassay in sixty-four diabetic patients. Of the sixty-four, twenty-seven had mild or moderate and thirty-seven had severe carbohydrate intolerance. Of those with moderate diabetes, eleven (41 percent) showed a normal degree of insulin rise, but in eight this was delayed or prolonged. Seven patients (26 per cent) had an excessive insulin response, seven a flat response, and two a low rise with a delayed peak. Of the thirty-seven patients with severe diabetes, thirteen (35 per cent) had a normal degree of insulin rise, although this was prolonged or delayed in six. Only three patients (8 per cent) had an excessive response. Fourteen (38 per cent) had a flat response and seven (19 per cent) a low, delayed rise. Of ten ketotic patients studied, nine had a flat insulin response. Patients whose diabetes had been controlled either on diet or oral therapy, or on both, showed normal or excessive plasma insulin levels after oral glucose. Overweight subjects had higher plasma insulin levels than underweight subjects, but there was no correlation between the insulin levels and the degree of obesity. Mild carbohydrate intolerance was associated with a higher plasma insulin response than was severe carbohydrate intolerance.

Plasma insulin values during a 50 g. oral glucose tolerance test were measured by immuno-assay in 34 control subjects. Peak insulin levels occurred within the first 60 minutes and the fasting level was approached by 120 minutes. The insulin curve closely resembled the blood sugar curve and a significant correlation was found between the blood sugar and plasma insulin values at 60, 90 and 120 minutes after oral glucose. The results suggest that the wide range in plasma insulin response is due in part at least to variations in the blood sugar. The results also tend to confirm that immuno-reactive insulin is biologically significant.

SUMMARY Intravenous glucose (25 g.) tolerance tests were performed and plasma insulin levels were determined in 25 normal subjects. There was a direct correlation between the glucose disappearance rate (K value) and the plasma insulin level 10 min. after the glucose injection. Oral glucose (50 g.) tolerance tests were performed in 34 normal subjects with plasma insulin level estimations. The plasma insulin response was slightly greater than that after the intravenous tests although the difference was not significant at the 5% level. Both oral and intravenous tests were performed in the same subjects in 17 instances and the plasma insulin responses in both tests were compared. Nine subjects showed a higher peak insulin response after oral glucose, and eight after intravenous glucose. The intensity and time-course of the insulin response in each individual was similar whether the glucose was given orally or intravenously.

A six-year prospective study of 144 newly diagnosed, symptomatic diabetic patients aged 40-69 years showed that 21 (15%) required insulin therapy, commencing 1-61 months after diagnosis. The plasma insulin response to oral glucose was assessed at the time of diagnosis. All 12 patients with very low peak insulin response (less than or equal to 6 mU/l) required insulin therapy. Thirty-six patients had an intermediate insulin response (greater than 6 less than or equal to 18 mU/l); of these, 7 with a mean weight 88% (range 73-96%) of average body weight required insulin, while 29 with a mean weight 117% (range 98-158%) of average body weight, did not. Ninety-six patients had a peak insulin response (greater than 18 mU/l); 2 patients whose weights were 96% and 100% of average body weight, required insulin, while the remainder did not. Consideration of initial body weight and peak insulin response provides a useful prediction of the eventual need for insulin.

Analysis of the first six months of intensive dietary management of 57 maturity onset diabetics showed that a large proportion of such patients could be satisfactorily controlled without the need of either oral hypoglycaemic agents or insulin. A dietitian's assessment of the patient's adherence to the prescribed diet allowed groups of good and poor dieters to be selected. Among the poor dieters the plasma insulin and triglyceride levels were significantly increased though plasma glucose levels were not significantly higher. Dietary adherence may thus be an prognostic risk factor in this group of diabetic patients.

Glucagon release from isolated islets (collagenase digestion) in control and streptozotocin-treated diabetic rats was measured in varying glucose concentrations and in the presence or absence of added insulin. High glucagon release from diabetic islets was noted, and this glucagon release could not be suppressed by glucose. Incubation of diabetic islets with insulin, 1,000 μU./1 ml., suppressed glucagon release at high glucose concentrations. Addition of insulin to control islets had no effect, nor had the administration of insulin to diabetic animals before decapitation. It is concluded that insulin deficiency removes the normal glucose suppression of glucagon release and that the effect can be reversed by high concentrations of insulin.

Plasma-gastrin levels measured by radioimmunoassay were found to be elevated in two patients with phaeochromocytoma. Both the administration of phenoxybenzamine and the later removal of the tumour reduced the fasting plasma-gastrin level to normal. The intravenous infusion of adrenaline in dogs produced a rise in plasma-gastrin level. It is concluded that catecholamines stimulate gastrin release.

Two hundred and twenty-three newly-diagnosed symptomatic diabetic patients with onset age 40-69 years enrolled in a prospective study of intensive dietary management of diabetes were observed for a period of six years and the data obtained is analysed. The variables studied were weight and fasting levels of plasma glucose and insulin, and of serum total cholesterol and triglyceride. These tests were monitored throughout the study and in addition the oral glucose tolerance test was analysed at entry to the study, after six months intensive dietary management and again after 72 months. Blood pressure, electrocardiogram and the presence of posterior tibial artery pulsation were recorded at entry to the study and at 36 months and 72 months. Approximately 80 per cent of the patients were managed solely by dietary restriction for the entire six years, but 25 patients received oral hypoglycaemic drugs and 26 required insulin treatment. Weight, and fasting glucose and triglyceride values fell in the first few months of intensive dietary management. Analysis of possible risk factors in survivors and patients dead at six years showed no significant differences, apart from a higher mean age at diagnosis in those who died. During the six years of intensive dietary management the mortality from all causes in these diabetic patients was no greater than that for the general population of Northern Ireland.

Peptic ulcer is a common problem in advanced renal failure, but most drugs for ulcers are hazardous in this condition. In a small open study cimetidine was given to nine patients with acid hypersecretion and endoscopically diagnosed duodenal ulceration who were undergoing haemodialysis. The patients obtained good pain relief and suffered no serious side effects. Both basal and stimulated acid output fell considerably and the plasma gastrin response to food increased during treatment. Two patients with recurrent vomiting during haemodialysis had a striking response to cimetidine, which suggested that such vomiting may be acid-mediated in some patients. These preliminary results suggest that cimetidine may prove to be an advance in the management of peptic ulcer in uraemic patients.

Proliferation of adipose tissue adjacent to intrasplenic transplants of whole isogeneic neonatal rat pancreas has consistently been noted. In this study over a period of 18 months there was a progressive increase in the amount of fatty tissue in the vicinity of surviving transplants. Immunohistochemistry demonstrated the presence of insulin, glucagon, somatostatin and pancreatic polypeptide within islet cells in long term grafts. Electron microscopy demonstrated a close association between islets and lipid droplets. Ductal elements within the transplants survived and showed close association with endocrine cells, but exocrine pancreatic tissue degenerated rapidly. Radioimmunoassay of extracts from surviving transplants in isogeneic rats confirmed the presence of high levels of insulin and glucagon after transplantation. In contrast, allogeneic intrasplenic transplants of rat pancreas failed to survive and showed no evidence of adipose tissue proliferation. Furthermore, isogeneic intrasplenic transplants of both adult rat fat and adrenal gland also failed to demonstrate adipocyte proliferation. It would appear that the presence of both adipocytes and pancreatic endocrine cells, particularly B cells, are required for the proliferation of adipocytes at the graft site.

The reported incidence of gastrointestinal endocrine tumours is variable. In Northern Ireland circumstances allowing such an assessment are favourable with a central diagnostic laboratory and register established to collect data on tumours from a well-defined population of 1.5 million people. From 1970 to 1985, 368 cases were recorded of which 85 per cent were carcinoid tumours. The annual incidence of carcinoid tumours was 1.3 per 100,000 of the population and the majority occurred in the appendix (61 per cent). No patients presented with the carcinoid syndrome. The annual incidence for other tumours was 0.12 per 100,000 for insulinomas; islet cell tumours of unknown type 0.07; Zollinger-Ellison syndrome 0.05; and multiple endocrine neoplasia (MEN) 0.05. There were two cases of VIPoma, one glucagonoma, one neurotensinoma and one tumour producing ACTH. It is possible that some tumours are more uncommon than others because of difficulty in diagnosis.

This study has examined changes in gastrointestinal hormones induced by alcohol. Ten normal volunteers consumed an orange and carbohydrate-containing drink on two separate occasions, with and without 50g alcohol. There was a significant hyperglycaemia associated with alcohol ingestion but no difference was noted in insulin or gastric inhibitory polypeptide in the two groups. Gastrin release was stimulated by alcohol but pancreatic polypeptide release and N-terminal glucagon release were both suppressed by alcohol. There was no difference in release of secretin or C-terminal glucagon in either group.

The effect of a low-dose infusion of dopamine on basal circulating concentrations of insulin, glucagon and glucose in six healthy male subjects is reported. Dopamine (0.1 microgram/kg/min) or placebo was given intravenously for 60 minutes. During infusion of the catecholamine, circulating plasma dopamine was 3.46 +/- 1 ng/ml. No change in circulating concentrations of insulin, glucagon and glucose were seen during infusion of dopamine when compared with placebo infusion. It is concluded that dopamine acting at a D2 receptor is unlikely to be of physiological importance in regulation of basal pancreatic islet cell function in man.

When correction was made for hypoalbuminaemia, 23 of 50 ambulant patients with definite or classical rheumatoid arthritis were found to have hypercalcaemia. When these 23 patients were studied 6 months later, 7 had hypercalcaemia as defined by the correction factor for a low serum albumin level, and 6 of these patients had raised serum ionised calcium concentrations. Biochemical studies in the 23 patients indicated evidence of hyperparathyroidism, namely, hypophosphataemia, increased serum alkaline phosphatase, hyperchloraemia, and reduced tubular reabsorption of calcium. However, serum immunoreactive parathyroid hormone concentrations were normal. Only one patient had an abnormally low serum 25-hydroxy-vitamin D result: this patient had a high level of urinary D-glucaric acid and was receiving phenobarbitone for treatment of epilepsy. The biochemical features suggestive of parathyroid overactivity were particularly found in patients with raised serum calcium levels. The cause of hypercalcaemia in rheumatoid arthritis remains to be explained.

Fasting levels of 5 gut hormones were studied in 30 patients with advanced uraemia (CRF), 40 undergoing regular dialysis (RD) and 555 renal transplant patients (RT). Mean values of gastrin and total glucagon were markedly elevated in CRF and RD patients compared with 20 normal subjects; there were lesser elevations in pancreatic glucagon, insulin and vasoactive intestinal peptide (VIP). Secretin levels were unchanged. In RT patients, fasting levels of VIP and pancreatic glucagon had returned to normal, while levels of gastrin, total glucagon and insulin remained slightly elevated compared with controls. Food stimulated hormone levels were measured in 18 RD patients and compared with 18 controls. After eating, RD patients failed to show the late increase in total glucagon, or the suppression of VIP and secretin seen in normal subjects; the pattern of gastrin and insulin response was similar to controls, but after the initial increase plasma levels in RD patients tended to show a slower decline. Thus involvement of the gastrointestinal tract in uraemia is associated with functional disturbance of the endocrine system of the gut.