Biomedical subjects
Publications and source records attributed to D J Chisholm.
A young footballer with phaeochromocytoma showed classical exercise-induced symptoms. Noradrenergic clincial phenomena suggested an extra-adrenal site. The usefulness of urine metabolite estimation and of localizing procedures and the importance of preoperative alpha and beta blockade are stressed. Nitroprusside was used successfully to control hypertension during surgery. Unexplained fever after operation is reported.
In order to determine whether glucagon levels of diabetic subjects are suppressible, alpha cell responsiveness to acute insulin administration (0.1 units/kg intravenously) was determined in fourteen juvenile onset, healthy diabetic and eight control subjects. In the diabetics, insulin produced a significant but slow fall in blood glucose over 60 min (P less than 0.01). On the other hand, glucagon levels fell dramatically in all diabetics to undetectable levels (P less than 0.001). Only one diabetic became hypoglycaemic and he alone showed a rebound rise of glucagon at 60 min. The rate of fall of blood glucose in the diabetic subjects was not influenced by the basal glucagon level (r=0.13) or the rate of fall of plasma glucagon (r=0.04). The glucose and glucagon responses of control subjects to insulin administration were in sharp contrast to the diabetics: blood glucose levels fell rapidly to hypoglycaemic levels and were associated with a major rise in glucagon levels (mean rise 116 pmol/1, P less than 0.001). We conclude that alpha cell hyperfunction in human diabetes can be completely suppressed by insulin administration and is therefore not autonomous, and that the slow rate of fall of blood glucose following insulin administration in diabetics is not secondary to glucagon excess.
Clinical and biochemical variables were examined during two standardized, low-dose insulin regimens in seven subjects with diabetic ketoacidosis and one with hyperosmolar coma, in order to determine whether glucagon levels can be suppressed in ketoacidosis and whether hyperglucagonaemia influences the clinical and biochemical responses to treatment. Glucagon concentrations were significantly elevated (36.6-697.0 pmol/l) at presentation in all subjects. After institution of insulin treatment (4-8 u/h), glucose and glucagon levels decreased rapidly, and in five of the eight subjects glucagon levels reached undetectable concentrations (less than 3.0 pmol/l) during the initial treatment period. Further, neither plasma glucagon concentrations at presentation, nor the rate of glucagon decline during insulin treatment, appeared to influence the rapidity of the glucose decline or the persistence of the ketoacidosis. Thus, low-dose exogenous insulin suppresses glucagon secretion in diabetic ketoacidosis, and the changes in glucagon concentrations during treatment are unrelated to the clinical response.
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The effect of secretin on forearm metabolism (muscle compartment) was examined in the presence of low and high concentrations of insulin. Continuous infusions (30 min. duration) of secretin 12 ng/min. (SEC), insulin 160 ng/min. (INS) or these doses of insulin and secretin together (INS + SEC) were delivered into the brachial arteries of normal volunteers. SEC alone was without significant effect on forearm metabolism. INS as previously reported, stimulated glucose and potassium uptake and inhibited the output of some amino acids from the deep venous bed. The two hormones together (INS + SEC) increased maximum lactate (p less than 0.025) and alanine output (p less than 0.005) beyond that observed with INS alone. A marked calcium output occurred (p less than 0.001) with the combined infusion which was not observed with either hormone alone. Potassium metabolism with INS + SEC was similar to that observed with INS alone. These results suggest that these two hormones, acting in concert, stimulate glycolysis and net calcium efflux. This joint action of insulin and secretin may have a physiological role in the immediate postprandial period.
Continuous infusions of glucose (90 min duration) were given into the duodenum (ID), or the portal vein (IP), or a peripheral vein (IV) in conscious dogs, intact dogs, or dogs with portacaval anastomoses. In intact animals ID glucose tolerance was better than IV glucose tolerance, but IP glucose tolerance was not significantly different from IV glucose tolerance. Thus, the superiority of tolerance to ID glucose was not accounted for by relatively high levels of glucose in portal blood. IV glucose tolerance was not significantly affected by protacaval anastomosis with ligation of the portal vein, but ID glucose tolerance was markedly impaired. Disproportionate impairment in tolerance to enterically administered glucose in dogs with portacaval shunts, and the similarity of IP and IV glucose tolerance in intact dogs, suggest that both liver and the gut are important in determination of oral glucose tolerance through mechanisms that have little or no effect on responses to parenterally administered glucose. The results also suggest that the hepatic contribution is not dependent upon portal venous perfusion of the liver, and that a humoral interaction between the gut and the liver is involved which is not simply dependent on endocrine responses of the pancreas.
Effects of intravenous (IV) infusion of secretin during IV infusion of glucose were examined in normal men. Secretin was administered according to three schedules: with each schedule a comparable priming dose was delivered in the first minute, but this was followed by a maintained (120 min) infusion of secretin at a relatively high rate, or by maintained infusion at one-third that rate, or by brief (15 min) infusion at the lower rate. The lower infusion rate produced increments in secretin in the blood within the range attainable during endogenous secretion. By comparison with effects of glucose alone each secretin infusion enhanced the increments of immunoreactive insulin in the blood. Enhancement of the early release (0-5 min) of insulin was similar with each type of secretin infusion, but the integrated changes in insulin levels through the total infusion period were related to the total doses of secretin. With each dose of secretin glucose tolerance was improved but the three mean glucose curves observed during infusions of secretin were not distinguishable from one another in spite of widely different integrated insulin responses. Secretin did not modify suppression of immunoreactive glucagon or free fatty acids in the blood during hyperglycemia. The results suggest that the effect of continuous administration of secretin on glucose tolerance is not simply related to its integrated insulinotropic action. It is suggested that the effect may be highly dependent on enhancement of insulin secretion early in the response to glycemia, or that it may be due to effects of secretin on glucose production or disposal which are not mediated by insulin.
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The fasting serum level of gastrin was determined by radioimmunoassay in 41 normal subjects, 27 patients with duodenal ulceration, 12 patients with gastric ulceration, and 8 patients following "complete" vagotomy. The patients with duodenal ulceration had significantly higher serum levels of gastrin (1.3 +/- S.D. 0.7 ng./ml.) than normal subjects (0.4 +/- S.D. 0.3 ng./ml.), patients with gastric ulceration (0.4 +/- S.D. 0.4 ng./ml.), or post-vagotomy patients (0.15 +/- S.D. 0.2 ng./ml.).The gastrin secretion in both normal subjects and patients with duodenal ulceration was responsive to protein ingestion, but a larger incremental secretion of gastrin occurred in the latter group. Hyperglycaemia significantly suppressed the serum level of gastrin in both groups. The patients with gastric ulceration had fasting and postprandial serum gastrin levels not significantly different from normal subjects.
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The insulin release after an oral glucose load is both earlier and greater than would be expected from the glycemic stimulus. This augmentation of insulin release has been attributed to humoral factors from the gut. It has been previously demonstrated that secretin is released very rapidly after oral glucose and postulated that it acts as an early trigger to insulin release. This effect would not explain the magnitude of the peak insulin response which occurs about 30 min after peak secretin levels. The present studies, however, demonstrate an additional action of secretin which may explain this. To further study the role of secretin in insulin release in normal subjects, two consecutive 20 min intravenous glucose infusions were administered 150 min apart with and without an intervening secretin infusion (10 U) given to approximate serum secretin levels seen after oral glucose ingestion. A highly significant (P<0.01) potentiation of the insulin response to the post-secretin glucose infusion was observed. This occurred both when secretin was given 7 min or 25 min before glucose. In the latter case, serum secretin was undetectable during the glucose infusion. These studies demonstrate that secretin potentiates the glycemic release of insulin. Despite the augmented insulin response, no consistent change in blood glucose variation was observed. This is consistent with the suggestion that the facilitated disposal of an alimentary glucose load is not dependent solely on enhanced insulin secretion. Secretin appears to have a dual role in insulin release, an early direct stimulation followed by a prolonged potentiation of the glycemic stimulus. The potentiating effect is of such magnitude to suggest that secretin is the dominant factor in the enteric component of insulin release after an oral glucose load.
The gastrointestinal stimulus to the release of insulin has been investigated in man by the use of a radioimmunoassay for secretin. Serum secretin levels rose rapidly after the oral ingestion of glucose or protein and preceded the elevation of serum insulin. An intravenous infusion of highly purified secretin caused a release of insulin when the serum secretin levels were within the physiological range. Infusion of hydrochloric acid into the duodenum caused an elevation of serum secretin and serum insulin levels in normal subjects. A similar response of secretin and insulin was seen after intravenous infusion of pentagastrin even when the acid stimulus to the duodenum was prevented. The latter observation suggests that pentagastrin (and probably gastrin) releases secretin by a direct humoral effect which is later fortified by the arrival of gastric acid in the duodenum. These studies suggest that secretin participates in the augmentation of insulin release after oral stimuli, and that a rapid sequence of humoral events takes place, gastrin releasing secretin and secretin releasing insulin. Subsequently secretin release would be augmented by a local stimulus in the duodenum and insulin release by the rising level of blood glucose or amino acids. This humoral system, which could also involve other gastrointestinal hormones, would provide a mechanism for facilitating the release of insulin to coincide with the onset of metabolite absorption.
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