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Background Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides. Methods We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant. Results Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L−1] of VIP [patients 27 (2.1–85.5); controls 9.8 (0–34)] and NPY [patients 20 (0–110); controls 12 (5–19)] were higher in patients (P

Aims Previous work has described short-term variation in the circulating plasma level of atrial natriuretic peptide (ANP), but the mechanism remains unknown. Our aim was to investigate the role of cardiac innervation in this variability. Methods and Results Blood samples were obtained from the right atrium via a pulmonary artery flotation catheter every 2min over a 90min period. Seven patients who underwent cardiac transplantation by the standard biatrial technique (partial innervation) and ten patients who underwent transplantation by the bicaval technique (total denervation) were studied. ANP levels were measured by radioimmunoassay. The median ANP levels were somewhat higher in the biatrial group compared to the bicaval group [470 (150–1095) vs 216 (100–605) pg.ml−1; median (range); P =ns], and both were much higher than normal levels in the pulmonary artery (40 (24, 56) pgml−1; median and interquartile range). In both transplant groups circulating plasma ANP levels showed considerable variability. The median number of ‘peaks’ and ‘troughs’, as counted by visual inspection, were not significantly different between the two groups. Computer analysis identified 12–16 and 6–15 ‘pulses’ in the biatrial and bicaval group, respectively. Further analysis revealed that pulse amplitude, height and area were significantly higher in the biatrial compared to the bicaval group. Conclusion It would appear that variability of circulating plasma levels of ANP is preserved despite complete or partial cardiac denervation, and so a neural mechanism does not appear to account for such variation.

Hyperglycaemia slows gastric emptying in both normal subjects and patients with diabetes mellitus. The mechanisms mediating this effect, particularly the potential role of insulin, are uncertain. Hyperinsulinaemia has been reported to slow gastric emptying in normal subjects during euglycaemia. The purpose of this study was to evaluate the effect of euglycaemic hyperinsulinaemia on gastric emptying in Type I (insulin-dependent) and Type II (non-insulin-dependent) diabetes mellitus. In six patients with uncomplicated Type I and eight patients with uncomplicated Type II diabetes mellitus, measurements of gastric emptying were done on 2 separate days. No patients had gastrointestinal symptoms or cardiovascular autonomic neuropathy. The insulin infusion rate was 40 mU · m–2· min–1 on one day and 80 mU · m–2· min–1 on the other. Gastric emptying and intragastric meal distribution were measured using a scintigraphic technique for 3 h after ingestion of a mixed solid/liquid meal and results compared with a range established in normal volunteers. In both Type I and Type II patients the serum insulin concentration had no effect on gastric emptying or intragastric meal distribution of solids or liquids. When gastric emptying during insulin infusion rates of 40 mU · m–2· min–1 and 80 mU · m–2· min–1 were compared the solid T50 was 137.8 ± 24.6 min vs 128.7 ± 24.3 min and liquid T50 was 36.7 ± 19.4 min vs 40.4 ± 15.7 min in the Type I patients; the solid T50 was 94.9 ± 19.1 vs 86.1 ± 10.7 min and liquid T50 was 21.8 ± 6.9 min vs 21.8 ± 5.9 min in the Type II patients. We conclude that hyperinsulinaemia during euglycaemia has no notable effect on gastric emptying in patients with uncomplicated Type I and Type II diabetes; any effect of insulin on gastric emptying in patients with diabetes is likely to be minimal. [Diabetologia (1999) 42: 365–372]

In this study, the distributions of calcitonin gene-related peptide, neuropeptide Y, and α-atrial natriuretic peptide 1–28 immunoreactivity, were investigated within different regions of the guinea pig heart by utilising two different methods of tissue fixation for the immunocytochemistry. The results were compared with data obtained through radioimmunoassays. We observed similar concentrations and distributions of α-atrial natriuretic peptide in the right atrium, with results of radioimmunoassay and immunocytochemistry, but there were no myocytes containing α-atrial natriuretic peptide in the left atrium or ventricles with immunocytochemistry as opposed to radioimmunoassay. The immunoreaction obtained for neuropeptide Y was more intense in the right ventricle than left. Calcitonin gene-related peptide nerve fibres were about twice as abundant in the left atrium than in the right.

C CLARKE, CG BRENNAN, K RODGERS, RM DWYER, PPA SMYTH ENDOCRINE LABORATORY, DEPARTMENT OF MEDICINE AND THERAPEUTICS, UNIVERSITY COLLEGE DUBLIN, IRELAND he demonstration in extrathyroidal human tissues of the sodium iodide symporter (NIS) has raised the possibility that 1311, commonly used as a systemic therapeutic ablative agent in hyperthyroidism and thyroid cancer, might be applied in the treatment of tumours in other NISexpressing tissues such as human breast cancer. Thyroidal transport of 1311 is known to be proportional to circulating stable I and the aim of this study was to determine how stable I (KI) would effect such transport in human breast cancer cell lines MDA-MB-231, MCF-7 and in FRTL-5 thyroid cells. All cells were incubated with KI (01 00mM) for 72 hours after which 1Th I was added . Incubation and uptake of 'l by cells was counted every four hours. Timed efflux of '^I was measured every five minutes. KI in the incubation medium blocked 1251 uptake in a dose-dependent manner in the E receptor positive MCF7 cell line. The effect was less marked in the E receptor negative MDA-MB-231 with significant uptake being maintained even at an I concentration of 50mM. A similar blockade was seen in the FRTL-5 cells with maximum uptake blockade of 25mM I. The rate of efflux of 15I was similar in both MCF-7 and MDA-MB-231 cell lines with a tin of 35 and 40 minutes respectively. In contrast, efflux from the FRTL-5 cells was faster (tire=15 mins). As the human breast has a much lower avidity for I than the thyroid, control of dietary intake would assume even greater importance in radioactive iodine treatment of breast tumours or their metastases.

Objective The somatostatin analogue octreotide (Sandostatin, Novartis, Basie) significantly improves the syndromes suffered by most patients with neuroendocrine tumours (NETs). The use of [111In-DTPA-D-Phe1]-octreotide scintigraphy ([111In]-pentetreotide) to predict the response to octreotide treatment has been described. Short-term hormone inhibition by a single injection of octreotide has also been reported. This study aimed to compare the effects of the suppression test with the response to long-term somatostatin analogue treatment, and to seek a correlation between the short-term suppression test, [11In]-pentetreotide observations and long-term somatostatin analogue treatment. Design and measurements Short octreotide suppression test and octreotide scintigraphy. Blood samples were collected before (0900, 0930 h), at (1000 h), and after (1030, 1100, 1200, 1300 h) the injection of 50 micrograms octreotide subcutaneously. Plasma hormones relevant to the syndrome were analysed by radioimmunoassay. The short suppression effects, the [111In]-pentetreotide observations and the response to long-term treatment with somatostatin analogue were evaluated and compared. Patients Twenty-six patients with metastatic NETs were evaluated, including 14 carcinoid tumours, 10 pancreatic endocrine tumours and 2 medullary carcinomas of thyroid (MCTs). Twelve patients had received octreotide treatment before the study, another 4 patients were treated subsequently with somatostatin analogue. Results During the short suppression test, hormones relevant to the syndromes were suppressed in 24 patients (those with carcinoids and pancreatic endocrine tumours). There was no suppression in the 2 patients with MCT. [111In]-pentetreotide observations closely correlated with the short suppression response to octreotide. Fourteen patients were treated with somatostatin analogue, and responded clinically; they had a positive short inhibition test and positive tumour uptake. Two patients with MCT did not respond to the treatment and had a negative suppression test and a negative [111In]-pentetreotide. Conclusion Our results suggest that a consistent relationship exists between the short suppression test and the response to somatostatin analogue treatment in the majority of the patients with neuroendocrine tumours. The octreotide suppression test and octreotide scintigraphy together will be helpful in selecting appropriate patients for clinical treatment with somatostatin analogues.

OBJECTIVE The hemodynamic, respiratory, and metabolic responses to exercise were studied in IDDM patients and control subjects to detect diabetic cardiomyopathy. RESEARCH DESIGN AND METHODS Eight subjects aged 25–40 years with diabetes of at least 10 years' duration were compared with eight control subjects aged 21–46 years. All subjects underwent a progressive incremental bicycle exercise test with measurement of gas exchange, blood glucose, lactate, fat metabolite, and catecholamine levels and two steady-state exercise tests with measurement of cardiac output by a CO2 rebreathing method. A new first-pass radionuclide method was used to measure cardiac ejection fractions (EFs) at rest, peak exercise, and steady-state exercise. RESULTS The peak achieved oxygen consumption was similar in the diabetic and control subjects (29.9 [25.1–34.6] and 31.4 [26.9–35.9] ml . min−1 . kg−1, respectively; mean [95% CI]). There were no significant differences in heart rate, double product, ventilation, respiratory exchange ratio, or ventilatory equivalents for oxygen and CO2 during the incremental test. Glucose levels were higher in the diabetic subjects, but there were no significant differences in levels of lactate, catecholamines, free fatty acids, glycerol, or β-hydroxybutyrate. Left ventricular EF fell from rest to peak exercise within the diabetic group (66.0% [59.6–72.4] at rest; 53.6% [45.6–61.6] at peak; P < 0.05) but this did not differ significantly from the control group (58.7% [52.3–65.1] at rest; 60.3% [48.9–71.7] at peak). Right ventricular EFs were similar in each group, and there was no reduction in peak filling rate to suggest diastolic dysfunction. The cardiac output responses to exercise were also similar in the two groups. CONCLUSIONS There is no evidence of impairment of the exercise response in subjects with long-standing diabetes, and the apparent fall in left ventricular EF at peak exercise could be related to hemodynamic adaptation.

We have previously shown an increased incidence of alpha-subunit-producing thyrotroph tumors after salmon calcitonin (sCT) injection into rats. However, it is not clear whether the effects of CT are direct or indirect. Our hypothesis was that for sCT to act directly, it must have a binding site on thyrotrophs. The alpha TSH cell line was used as a model for thyrotrophs. Receptor binding studies using alpha TSH membranes revealed a high affinity binding site for sCT [IC50 = 0.97 +/- 0.18 nM (n = 4); Kd = 5.45 +/- 0.43 nM (n = 3); binding capacity = 6.6 pmol/mg protein (n = 3)]. Rat CT did not compete with binding at this site. Receptor screening for other CT peptide family members revealed high specific binding for CT gene-related peptide (CGRP; IC50 = 0.25 +/- 0.08 nM; n = 3) and islet amyloid polypeptide (IC50 = 4.36 +/- 1.1 nM; n = 3). This together with the absence of rat CT binding excluded a conventional CT-binding site, and we propose a site similar to the CGRP subtype III receptor described in the rat nucleus accumbens. Guanosine 5'O-(3-thiotriphosphate) (GTP gamma S) (20 microM), reduced [125I]CGRP binding to 38% of maximal, indicating that this site is G-protein coupled. Immunocytochemically, all of the cells displayed intense sCT-like immunoreactivity, which was totally abolished by preabsorption of the antibody with sCT. The presence of this receptor supports the hypothesis that sCT mediates tumorigenesis via a direct pituitary action and, together with the coexistence of a sCT-like peptide in these cells, provides evidence for a possible autocrine role of this peptide in the control of thyrotroph function.

Peripheral circulating levels of atrial natriuretic peptide may exhibit short-term variation compatible with a pulsatile pattern of secretion. We obtained samples every 2 min for 90 min from the antecubital vein of 16 patients with chronic cardiac failure and 13 controls. Overall levels were higher in the patients (median and quartiles 230 (125,325) vs. 26 (16,48) ng l-1; P0.001). In both groups there was considerable variability, with 10 (2-12) peaks, 9 (7-15) troughs (both defined as2 SD from the mean) and 16 (13-18) pulses (defined by computer) during the sampling period in controls, and a similar number in patients. We then carried out simultaneous sampling in the pulmonary artery, femoral artery and peripheral vein in eight subjects with normal cardiac function and six patients with impaired function due to valvular heart disease. The pattern of variability was preserved in all three sites in both groups, suggesting intermittent secretion rather than variable breakdown of the peptide in the lung. No changes in right atrial pressure or heart rate were observed to coincide with the variations, but levels of the peptide in the pulmonary artery correlated with right atrial pressure in patients (r = 0.87; P0.05). The mechanism of such periodicity and its pathophysiological importance remain unknown.

The effect of dietary fats on gastrin in the pyloric antrum and plasma of Wistar rats was examined. Two different age-groups of rats were fed on three different diets in which fat was in the form of menhadenoil (MO), hydrogenated coconut oil (CO) and safflower oil (SO) respectively. Control groups were fed on normal laboratory diet. Each diet was isoenergetic and no group showed significant differences in either food intake or weight gain during the experiment. Weaner rats fed on the MO diet exhibited significant reductions in both antral (P= 0.047) and plasma (P= 0.002) gastrin concentrations when compared with age-matched controls. Likewise, adult rats fed on the MO diet exhibited significant reductions in both antral (P= 0.008) and plasma (P= 0.002) gastrin concentrations. In addition, adult rats fed on the CO diet exhibited significant reductions in both antral (P= 0.047) and plasma gastrin(P= 0.002) concentrations. Rats from both age-groups fed on the SO diet exhibited no significant differences in gastrin concentrations when compared with their respective control groups. These findings indicate that the composition of dietary fat can have profound effects on both tissue and plasma concentrations of gastrin in rats.

A pilot study on exocrine pancreatic function, using the 2-day para-aminobenzoic acid (PABA) test, was performed on 21 healthy elderly and 26 healthy young subjects. A PABA excretion index (PEI) less than 55%, indicating moderate to severe exocrine pancreatic insufficiency (EPI), was found in 19% of the elderly group (95% confidence limits 5-42%). While the mean value of the PEI was significantly lower in the elderly compared with the young group (Mann-Whitney Z = 2.8, p less than 0.01), there was no significant difference when the elderly subgroup with PEI less than 55% was excluded. There was no evidence of a generalized moderate to severe decline in pancreatic exocrine function with increasing age; a mild to moderate decline cannot be excluded.

Sprague–Dawley rats (3 weeks old) were fed on isoenergetic diets in which 40 % of the total energy was provided as fat either in the form of butter (high saturated fat), olive oil (high monounsaturated fat) or maize oil (high polyunsaturated fat), with one group on low-fat (10% of total energy) standard diet as a control. Animals were killed after 8.4 (se 0.8) weeks by cardiac puncture. Similar pieces of jejunum and ileum were prepared for morphometric studies. Extracts of tissue from the proximal and distal segments of the whole small intestine from four animals per group were assayed using established techniques for enteroglucagon, motilin, neurotensin, somatostatin, substance P and vasoactive intestinal peptide (VIP). We found that maize oil and olive oil increased villus height: crypt depth ratio in both jejunum and ileum. Maize oil increased tissue concentrations of somatostatin (P< 0.05) and substance P (P< 0.005) in the proximal segment. Both maize oil and olive oil increased tissue concentrations of neurotensin and substance P (P< 0.005) in the distal segments. These observations may explain the improvement of intestinal absorption of fluid following supplementation with polyunsaturated fat

Autoantibodies arise when there is a breakdown in immunological tolerance. Autoantibodies to parietal cells and intrinsic factor are found in autoimmune atrophic gastritis (AAG) and are associated with elevated plasma gastrin. Endogenous gastrin autoantibodies have not been described to date. The aim of this study was to investigate the occurrence of autoantibodies to gastrin. Plasma from 50,000 patients, including more than 2000 with AAG, was tested. Gastrin was measured by radioimmunoassay (RIA) in whole plasma and the presence of autoantibody determined by using a control which omitted assay antibody. The quantity and affinity of gastrin autoantibodies was assessed. Three patients had autoantibodies to gastrin. All three had AAG and pernicious anaemia (PA). The antibodies were of low titre and relatively high affinity. Free circulating plasma gastrin levels were within the normal range, but total gastrin levels were elevated. This is the first description of autoantibodies to endogenous gastrin. The incidence of antibodies to gastrin is low, they are found in association with PA, and they may lead to falsely low measurements of plasma gastrin.

Several studies have shown that hyperglycaemia slows gastric emptying in normal subjects and patients with diabetes mellitus but whether hyperinsulinaemia per se has an effect remains debatable. In the present study we have assessed the effect of hyperinsulinaemia on gastric emptying of a solid and liquid meal in normal subjects. Ten men were studied three times in random order. After an overnight fast, subjects were infused with 0.9 % NaCl on two occasions and on the third with insulin, at 40 mU · m−2· min−1 with 20 % glucose simultaneously to maintain euglycaemia. Steady-state glucose infusion rate was ensured before the subjects ate a standard meal of a pancake labelled with 99mTc and milkshake labelled with 111In-DTPA. Gamma-scintigraphic images were then obtained every 20 min for the next 3 h. There were no significant differences between the mean half-emptying times (T50) of the solid and liquid during the two saline infusions (129.6 ± 28.5 vs 128.4 ± 23.8 min for the solid and 25.4 ± 7.0 vs 34.7 ± 18.0 min for the liquid, mean ± SD). Hyperinsulinaemia delayed both solid (mean T50 149.6 ± 30.7, p = 0.031) and liquid emptying (mean T50 39.8 ± 13.9, p = 0.042). There were no significant differences in the cholecystokinin and glucagon-like peptide 1 responses to the meal during either saline or insulin infusions. There was a tendency towards a greater insulin response to the meal during the hyperinsulinaemic study. Thus, hyperinsulinaemia delayed emptying of both the solid and liquid components of the meal. [Diabetologia (1998) 41: 474–481]

Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are known to be elevated in patients with chronic heart failure at rest. While it is known that during exercise the circulating level of ANP increases in patients with heart failure, the response of BNP to exercise in these patients relative to control subjects is unclear. Ten patients with stable chronic heart failure and 10 normal control subjects performed symptom-limited exercise with respired gas analysis. All patients had depressed left ventricular ejection fractions (LVEF). Patients had lower peak oxygen consumption PVo 2 ) than the control group [median (range) 1.18 (098-1.76) vs. 1.94 (1.53-2.31) L min -1 ; P < 0.001]. Circulating plasma levels of ANP and BNP were higher at rest in patients than in control subjects [ANP 335 (140-700) vs. 90 (25-500) pg mL -1 ; BNP 42 (25-50) vs. 20 (10-20) pg mL -1 ], and at peak exercise [ANP 400 (200-1000) vs. 130 (10-590); BNP 46 (40-51) vs. 20 (10-30)]. The rise in ANP at peak exercise was significant in patients compared with the resting level, but not in control subjects. For BNP, there was a significant rise in patients but no change in control subjects. The circulating plasma levels of both peptides showed a strong negative correlation with LVEF (ANP, P < 0.005; BNP, P < 00001) and, to a less extent, with RVEF. It is possible that BNP may give a better indication of cardiac function.

Aims Candoxatril is a specific neutral endopeptidase (NEP) 24.11 inhibitor, and previous work has documented the effect of NEP inhibition on atrial and brain natriuretic peptides (ANP, BNP). The aim of the present study was to ascertain the effect of NEP inhibition on circulating levels of vasoactive peptides. Methods We studied seven patients with chronic heart failure who were randomized to receive candoxatril, candoxatril/captopril, captopril and placebo in a four way cross over, double-blind pattern. Results The mean circulating level of endothelin (ET) was increased 2 h after placebo (10 to 20 pg ml−1 ) and also calcitonin gene-related peptide (CGRP) (27 to 51 pg ml−1 ), but ANP levels changed little during this time (73 to 75 pg ml−1 ). Following candoxatril, however, ET (10 to 39 pg ml−1, P

Medullary thyroid carcinoma (MTC) is an APUDoma (APUD refers to amine precursor uptake and decarboxylation) arising from the parafollicular cells. Diarrhoea has been reported in some 30% of patients, variously attributed to excess production of calcitonin (CT), serotonin (5-HT), vasoactive intestinal peptide (VIP) or other factors. The regulatory factors in MTC were examined employing immunocytochemistry and RIA to tumours and their extracts. The patients were followed up for more than 15 years. CT and calcitonin gene-related peptide were universally expressed in all the tumours. The neuroendocrine markers chromogranin A (and its fragments pancreastatin and WE-14), neurone-specific enolase, protein gene product 9·5 and carcino-embryonic antigen were found in the majority of MTCs and might be useful as immunocytochemical markers. 5-HT, substance P, neurokinin A, glucagon and VIP could not be detected, excluding them as candidates in the diarrhoea of MTC. Journal of Endocrinology (1997) 152, 275–281

In 1993, a Japanese group reported the occurrence of a potent vasodilator peptide in acid extracts of a human phaeochromocytoma, using the activity of rat platelet cAMP activity as a biological assay, followed by HPLC purification and amino acid sequencing. The peptide consisted of 52 amino acids, had one intramolecular disulphide bond and an amidated C-terminal tyrosine, and was named adrenomedullin (AM). When AM was injected intravenously (3 nmol/kg) into rats, it resulted in a fall in blood pressure, lasting for 30-60 min. This was comparable to the hypotensive activity of calcitonin gene-related peptide (CGRP) (which is established as one of the strongest vasodilators). These findings led to the conclusion that AM is a potent and long-acting hypotensive peptide, with a putative role in blood pressure control.

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.

1. Plasma concentrations of gastrin, glucose, vasoactive intestinal polypeptide and non-esterified fatty acid were analysed in six male endurance runners and six male hockey players before, during and 15 min after 90 min treadmill running at 65% maximum oxygen uptake under two conditions: no fluid ingestion (trial A) and ingestion of 8% maltodextrin solution (trial B). 2. Exercise resulted in significantly elevated plasma gastrin concentrations compared with resting values in both groups after trial A (endurance runners, 69.4 ng/l; hockey players 71.4 ng/l) and trial B (endurance runners, 105.5 ng/l; hockey players, 83.2 ng/l). The gastrin response was not significantly different between the trials. 3. Plasma vasoactive intestinal polypeptide levels increased significantly beyond resting levels for both groups during trial A (endurance runners, 76.1 ± 53.7 ng/l; hockey players 155.6 ± 41.9 ng/l) and trial B (endurance runners 47.5 ± 21.3 ng/l; hockey players 132.9 ± 43.9 ng/l). The vasoactive intestinal polypeptide response to trial B was significantly attenuated compared with trial A. 4. There were no significant differences between endurance runners and hockey players for plasma gastrin, although hockey players produced significantly elevated concentrations of plasma vasoactive intestinal polypeptide after both trials compared with endurance runners. 5. Plasma glucose levels throughout trial B were significantly greater than after trial A irrespective of the group. Plasma glucose concentrations were not significantly different between endurance runners and hockey players. 6. Plasma non-esterified fatty acid concentrations rose significantly for both groups throughout exercise. Trial B resulted in an attenuated non-esterified fatty acid response compared with trial A. 7. No significant relationships were identifed between metabolite and gastrointestinal hormone concentrations, or between maximum oxygen uptake and the hormonal response to exercise. 8. These results highlight the attenuating role of carbohydrate fluid ingestion and level of aerobic fitness in the responses of plasma vasoactive intestinal polypeptide during prolonged exercise, whereas plasma gastrin is not significantly affected by either.

To determine if exercise intolerance and fatigue in chronic heart failure could be exacerbated by an abnormal metabolic response to exercise, we studied 12 patients with stable chronic heart failure and 12 normal volunteers during symptom-limited maximal treadmill exercise. Peak VO2 was 17.2 (15.1-19.2) ml.kg-1 x min-1 in patients and 29.9 (26.3-33.5) in controls (mean and 95% confidence intervals; P < 0.0001, t-test). Overall, levels in peripheral venous blood of glucose, glycerol and free fatty acids were greater in patients, although the differences became less marked with increasing exercise intensity. Noradrenaline was elevated in patients at rest, but the peak exercise response was similar to controls. Responses of adrenaline, insulin and glucagon were similar in both groups. We conclude that depletion of the levels of circulating substrates is not contributory to exercise intolerance and fatigue in chronic heart failure. Greater levels of glycerol and free fatty acids may be mediated by excess sympathetic nervous system activity, reflected in elevated noradrenaline levels.

To investigate the role of muscarinic cholinergic mechanisms in mediating the pancreatic and pituitary hormonal responses to hypoglycaemia, six normal subjects were studied during acute insulin-induced hypoglycaemia under control conditions, and during blockade with intravenous atropine. During atropine blockade the response of pancreatic polypep-tide was suppressed while the maximum response of plasma glucagon was significantly higher. The increment in plasma vasopressin was also increased significantly during cholinergic blockade. During blockade with atropine the responses of plasma prolactin was reduced, with a slight but significant reduction in the growth hormone response, and although a similar maximum response of plasma ACTH was achieved, this rise was delayed. These results implicate involvement of a cholinergic muscarinic inhibitory and stimulatory mechanisms in regulating the responses of pancreatic and pituitary hormones to hypoglycaemia.

Gastric inhibitory polypeptide (GIP), a hormone secreted from the proximal small gut, is recognized as a major component of the enteroinsular axis. However, circulating levels of GIP in diabetes have been reported to be exaggerated, normal or decreased following glucose ingestion, which may be due to the presence of variable crossreacting immunoreactive GIP forms in the circulation. We have raised an antibody (S705) which recognizes only 5 kDa GIP. Using this antiserum we have measured circulating GIP levels in 18 healthy volunteers, and 13 Type 2 diabetic and 9 Type 1 diabetic patients following ingestion of 75 g glucose. As expected, blood glucose levels and blood insulin levels are significantly abnormal in the diabetic groups. On the other hand, circulating GIP levels at all time-points and integrated incremental GIP over 120 min were not different from the control group. However, we cannot exclude the possibility that apparently normal immunoreactive GIP levels in diabetes might conceal subtle alterations in biological activity which could play a role in the pathogenesis of the disease.

Twenty-five patients with acute severe asthma were treated with oxygen, corticosteroids and either salbutamol or aminophylline by intravenous infusion. Blood glucose, plasma insulin and glucagon were measured during the first 24 hours of treatment. Salbutamol and aminophylline rapidly caused hyperglycaemia, accompanied by a rise in insulin and a fall in plasma glucagon. At first the increase in plasma insulin was insufficient to restore normoglycaemia, but by 24 hours homeostasis was restored. The early submaximal insulin response was attributed to the fasting caused by breathlessness. There was no evidence of an increase in hormone secretion caused by direct beta 2-adrenergic stimulation of the pancreatic islets. The effect of corticosteroids on blood glucose over the period of study was considerably less than the contribution of either salbutamol, or aminophylline.

A good prognosis in medullary thyroid carcinoma (MTC) has been correlated with homogenous immunohistochemical staining using antibodies to calcitonin (CT). Also, for unexplained reasons, multiple endocrine neoplasia (MEN) 2A and sporadic MTC patients had a better prognosis than MEN 2B patients. However, the post-operative serum CT level was not helpful in predicting the prognosis. The aim of this work was to reassess the prognostic factors in MTC, employing these three parameters in 16 patients (6 MEN 2A and 10 sporadic) for a period of more than 15 years. Normalization of post-tumour resection serum CT was associated with significant improvement of survival (P=0.0009) and in the quality of life (P=0.0002). In accordance with previous reports, MEN 2A patients had a better prognosis than sporadic patients. The pattern of immunohistochemical staining was not helpful in assessing prognosis. We conclude that normalization of post-operative serum CT is a helpful and practical tool in

In vivo and in vitro techniques have been used to study the effect of catecholamines on gastrin release. The i.v. infusion of epinephrine in dogs produced a significant rise in plasma gastrin concentration. This response was prevented by the administration of propranolol to block beta-adrenergic receptors. The infusion of isoproterenol, a beta-adrenergic agonist, produced a significant rise in gastrin levels, while phenylephrine, an alpha-adrenergic agonist, had no effect. In in vitro studies using isolated pieces of rat antrum, isoproterenol stimulated acute phase release of gastrin, whereas phenylephrine was again without effect. The studies indicate that catecholamines directly influence G cell function.

Abnormal gastric motility has been recognised recently in some patients with excessive gastro-oesophageal reflux. The cause of this motility disturbance is unknown. A dual isotope study has been used to assess gastric emptying of solid and liquid components of a test meal in 16 patients with erosive oesophagitis and in 16 control subjects. The release of insulin, gastrin, pancreatic polypeptide, gastric inhibitory polypeptide and neurotensin in response to the test meal was monitored in all subjects. A significant delay in both solid and liquid emptying was observed in patients with erosive oesophagitis. However, they demonstrated no alteration in the pattern of hormone release in response to the test meal.

Redmond, A. O. B., Buchanan, K. D. and Trimble, E. R. (The Royal Belfast Hospital for Sick Children, Belfast, and The Department of Medicine, Queen's University, Belfast). Insulin and glucagon response to arginine infusion in cystic fibrosis. Acta Paediatr Scand, 66:199, 1977.—The glucagon and insulin responses to intravenous arginine were studied in 17 children with cystic fibrosis and in 9 control children. It was found that the overall secretion of insulin was diminished; however, four of the CF children did have a normal output. The glucagon responses did not parallel those of insulin. The glucagon output varied in the CF children—seven had normal, four excessively high and six low output. Three of the four children with extremely high output had more severe disease and were below the third centile on the weight chart. These four had a fasting hypoglycaemia and also a very low glucose and insulin response. We have confirmed diminished insulin secretion in cystic fibrosis, but diminished glucagon secretion was only noted when some insulin secretion was preserved. The high levels of glucagon seen in the most insulin deficient subjects may be derived from extrapancreatic sources, or may be associated with ‘stress‘ reaction in these patients who also had most severe pulmonary involvement. The data would be consistent with diminished glucagon and insulin secretion from the pancreas but as the disease progresses an excessive secretion of extra pancreatic glucagon results.

Serum trypsin-like immunoreactivity and pancreatic isoamylase were measured in 302 insulin-dependent diabetic patients (166 men) using radioimmunoassay for the former and a photocolorimetric method for the latter. There was a significant correlation between the two enzymes (r = 0.67, p less than 0.0001) with lower concentrations of both trypsin-like immunoreactivity (208.8 micrograms/L) and pancreatic isoamylase (67.5 U/L) in diabetic patients as compared to controls (p less than 0.0001). Using multiple regression analysis, a statistically significant association was only apparent between enzyme concentrations and age at onset of diabetes (r = 0.31, p less than 0.0001). The results suggest that impaired exocrine pancreatic function may occur in an appreciable proportion of diabetic patients and also that a primary insult to the exocrine pancreas occurring at the time of endocrine injury may be a contributory factor.

The purpose of this study was to evaluate the role of neurotensin in the local regulation of the lipid-induced jejunal hyperemia. Total blood flow and the arteriovenous hormone concentration difference were measured in isolated jejunal loops of anesthetized dogs with either saline, bile (10% in normal saline), oleic acid (40 mM in normal saline), or oleic acid and bile in the lumen. The bile-oleic acid mixture produced a sustained increase (+25 +/- 3%) in jejunal blood flow, whereas neurotensin release reached a maximum (1.14 +/- 0.34 pmol X min-1 X 100 g-1) 2 min after initiation of the response and then returned to control. Venous neurotensin concentrations also reached a maximum (51 +/- 17 pmol/l) at 2 min. There were no significant changes in either blood flow or neurotensin release in response to the other test solutions. Intra-arterial infusion of neurotensin did not significantly decrease jejunal vascular resistance (-12 +/- 3%) until venous concentrations of 478 +/- 101 pmol/l were attained. It seems unlikely, then, that neurotensin plays any role in the regulation of the lipid-induced jejunal hyperemia

The microtubule-disrupting drug vincristine is a common component of anti-cancer chemotherapeutic regimes, which produces acute constipation as a side effect. Although generally attributed to damage to the myenteric plexus, the precise mechanism of this disturbance is unknown. In addition, vincristine causes marked aberrations in the secretory response of pancreatic endocrine tissue in both man and rats. No information is available on its possible effect on regulatory peptides of the gastrointestinal tract. In this study we have produced vincristine-induced constipation in rats at a dosage comparable with that employed in the treatment of human subjects. Immunocytochemistry revealed concomitant disturbances in cells exhibiting immunoreactivity for gastrin in the antrum, for gastric inhibitory polypeptide and 5-hydroxytryptamine in the duodenum, for enteroglucagon in the colon, and for somatostatin in all three sites. These widespread effects are transient in nature with normal cell numbers and morphology being reestablished within 6 days. It is suggested that the observed effects are a direct result of microtubule disruption and that gastrointestinal regulatory peptide and amine immunoreactive cells have a rapid regeneration potential.

As gastric acid and pepsin inhibit blood coagulation and platelet aggregation it is surprising that most upper GI haemorrhages stop spontaneously. To investigate this paradox we have studied acid and pepsin secretion, gastric motility and GI hormones after simulated upper GI haemorrhage. In seven healthy volunteers intraduodenal infusion of 160 ml autologous blood decreased pentagastrin stimulated submaximal acid secretion (mmol/h) from 30.0 (3.2) (mean (SE] in the hour preceding infusion to 21.4 (3.7) in the hour following infusion (p less than 0.02), representing a mean reduction in acid output of 30%. Pepsin output (mg/h) was also decreased from 207.5 (67.7) (mean (SE] in the hour preceding blood infusion to 135.7 (54.7) in the hour after infusion (p less than 0.02) representing a mean reduction in pepsin output of 43%. In six volunteers gastric emptying of a liquid meal was delayed after intraduodenal blood infusion compared with intubation alone with the emptying time (min) to half volume (t 1/2) being prolonged at 75.0 (8.2) (mean (SE] after blood infusion compared with 35.5 (6.6) after intubation alone (p less than 0.02). Plasma GIP concentrations (ng/l) increased to peak levels of 127.9 (62.7) (mean (SE] after intraduodenal blood infusion compared with the pre-infusion value of 58.3 (2.3) (p less than 0.02). These changes may represent protective physiological responses to facilitate haemostasis.

Plasma immunoreactive secretin levels were measured in 22 newly diagnosed non-ketotic, maturity-onset diabetics and 10 healthy control subjects during 50 gram oral glucose tolerance test (OGTT). The test was repeated in the diabetic group after 6 months' dietary treatment. At diagnosis the fasting secretin levels in the diabetics were higher than in control subjects but fell within the normal range following dietary treatment. In the diabetics there was a significant positive correlation between the fasting glucose and fasting secretin levels at the time of diagnosis. Suppression of secretin levels occurred during the OGTT, both in diabetic and control subjects.

The effect of duodenogastric reflux on systemic and portal venous blood concentrations of somatostatin has been studied in the dog. Duodenogastric reflux suppressed somatostatin concentrations in both systemic and portal venous blood, but this did not occur when bile alone was diverted into the stomach. The suppression was also much less marked when truncal vagotomy accompanied the reflux. These findings suggest that altered somatostatin activity may play a part in the production of the pathophysiological changes occurring in clinical conditions such as peptic ulceration, in which there is an increase in duodenogastric reflux.

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.