Effects of oxytocin delivery on counter-regulatory hormone response in insulin-dependent (type 1) diabetic subjects

In insulin-dependent (type 1) diabetic subjects (n = 7) with intact hormone response to hypoglycaemia, oxytocin infusion (0.2 mU/min over 60 min) produced significant rises in basal plasma glucagon and adrenaline levels, while it reduced basal plasma cortisol levels. During insulin-induced hypoglycaemia, oxytocin potentiated the increases in plasma glucagon and adrenaline, while an inhibitory effect on plasma cortisol levels was still present. In insulin-dependent (type 1) diabetic subjects (n = 7) with blunted counter-regulatory hormone response to hypoglycaemia, the same dose of oxytocin (0.2 mU/min over 60 min) increased basal plasma glucose and glucagon concentrations and lowered basal plasma cortisol concentration. In the same group of patients, oxytocin delivery (0.2 mU/min), simultaneously to an insulin-induced hypoglycaemia, produced a significant elevation of plasma glucagon and adrenaline concentrations thus enhancing glucose recovery from hypoglycaemia. In conclusion, in insulin-dependent (type 1) diabetic patients, oxytocin delivery enhances plasma glucagon and adrenaline levels in basal conditions and during insulin-induced hypoglycaemia.     

Defective blood glucose counter-regulation in diabetics is a selective form of autonomic neuropathy.

Administration of a low-dose insulin infusion to normal subjects results in a mild drop in blood glucose concentration (1.1 mmol/1 (20 mg/100 ml)) and the resetting of the basal glucose at the lower concentration. Clinical hypoglycaemia does not develop, and there is a significant release of glucagon, growth hormone, and cortisol. A similar infusion in insulin-requiring diabetics results in hypoglycaemia accompanied by a release of growth hormone and cortisol but no significant release of glucagon. Subsequently giving arginine to these patients results in a significant release of glucagon, indicating that the alpha cell is intact and can respond to local, direct stimulation. In one patient the defect in glucagon response to impending hypoglycaemia developed after two years'' insulin treatment. This type of dissociated response'' of the alpha cell has been reported in animals after denervation of the pancreas, and insulin-requiring diabetics may develop a selective form of autonomic neuropathy affecting the vagal control of glucagon release.     

Suppression of basal plasma cortisol and adrenal androgen concentrations, but not of ACTH and cortisol responses to hCRH by low-dose dexamethasone in rhesus monkeys

Glucocorticoid treatment at replacement doses does not result in a suppression of ACTH and cortisol responses to corticotropin-releasing hormone (CRH), while basal plasma concentrations of cortisol and adrenal androgens are efficiently suppressed 34 h after starting treatment. This finding could be demonstrated in rhesus monkeys receiving a continuous infusion of dexamethasone (1 microgram/kg per h) for 48 h and confirms our observations in patients on alternate-day prednisone therapy and in patients with congenital adrenal hyperplasia on glucocorticoid replacement therapy. We conclude that the decrease of basal adrenal steroid secretion resulting from glucocorticoid replacement therapy represents an effect on hypothalamic rather than on pituitary function.     

Glucose turnover and metabolic and hormonal changes in ethanol-induced hypoglycaemia.

Infusion of 67 g ethanol over four hours in fasted, non-obese normal men (a) induced hypoglycaemia by inhibiting gluconeogenesis; (b) produced noticeable increases in blood lactate, 3-hydroxybutyrate, and free fatty acid concentrations; (c) depressed plasma growth hormone concentrations, despite hypoglycaemia; and (d) raised plasma cortisol concentrations before significant hypoglycaemia occurred. These metabolic changes were explained by the reduction of redox state which accompanies ethanol oxidation. The pronounced changes in metabolic values recorded during this study suggested that the use of parenteral feeding regimens including ethanol needs to be reconsidered.     

Effects of alpha-2 adrenoreceptor blockade by yohimbine on the hormonal response to hypoglycaemic stress in normal man

In order to evaluate the effect of alpha-2 adrenoreceptor blockade on the ACTH response to insulin-induced hypoglycaemia, six normal men were studied with and without yohimbine (30 mg p.o.) premedication. Despite a similar hypoglycaemic stimulus and significant suppression of the growth hormone response (P less than 0.05), no change was observed in basal or stimulated plasma ACTH, cortisol, arginine vasopressin (AVP) or prolactin responses following yohimbine. We conclude that alpha-2 adrenoceptor blockade with yohimbine does not significantly affect the ACTH response to hypoglycaemia in man.     

Relative potency in acute and chronic suppressive effects of prednisolone and betamethasone on the hypothalamic-pituitary-adrenal axis in man

The relative potency in the hypothalamic-pituitary-adrenal (HPA) suppression of both prednisolone and betamethasone was examined in an acute study with normal volunteers and in a chronic study with glucocorticoid-treated patients. Circadian rhythm of plasma cortisol was studied after a single dose administration of 5 to 30 mg prednisolone or 0.5 to 3.0 mg betamethasone at 8:00 hr. Morning-rise of plasma cortisol occurred on the morning after the administration of 30 mg or less prednisolone but no morning rise was noted after the administration of 1.0 mg or more betamethasone. Plasma ACTH was slightly elevated on the morning after 30 mg prednisolone administration but showed low levels throughout the night after 3.0 mg betamethasone administration. Plasma cortisol responsiveness to ACTH was examined in patients before and during therapy with either prednisolone or betamethasone. The basal cortisol level was not suppressed and the responsiveness to ACTH remained nearly normal during long-term 5 mg prednisolone therapy, but these were completely suppressed during long-term 5 mg betamethasone therapy. The responsiveness to ACTH was nearly normal in patients receiving alternate-day therapy with prednisolone in such large doses as 50 or 60 mg every other day, but was completely suppressed in patients receiving 1.0 mg betamethasone every other day. The relative potency of betamethasone in acute and chronic suppressive effects on the HPA system seems to be much stronger than that of prednisolone in equivalent doses with comparable anti-inflammatory effects. It is also suggested that the alternate-day therapy with such long-acting steroids as betamethasone are useless in preventing HPA suppression.     

Hypoglycaemia-insulin test: discordant growth hormone and cortisol response in paediatric patients regarding recovery from hypoglycaemia with or without oral glucose solution

BACKGROUND: Hypoglycaemia-insulin test (HIT) is the 'gold standard' for the diagnosis of adrenal-pituitary-hypothalamic axis disorders. Controversy exists on the convenience of recovery from an insulin-induced hypoglycaemia since this test is not risk-free. OBJECTIVE: To ascertain whether recovery from insulin-induced hypoglycaemia with an oral glucose solution produces a different response of growth hormone (GH) and cortisol at different times of the study compared with spontaneous recovery from hypoglycaemia. PATIENTS AND METHODS: Prospective study of 100 children and adolescents with growth delay who underwent an HIT. Patients were consecutively assigned to two groups of 50. In one group recovery from hypoglycaemia occurred spontaneously and in the other recovery was achieved with an oral glucose solution (20 g of glucose) when glycaemia was under 30 mg/dl. The two groups did not differ in age, sex, pubertal status, weight, height and IGF-I levels. RESULTS: The response of GH at 30, 60, 90 and 120 min and cortisol at 10, 60, 90 and 120 min was lower and statistically significant in patients with recovery from hypoglycaemia with oral glucose solution. GH deficiency was diagnosed more frequently in patients recovered with glucose solutions (94%) compared to those with spontaneous recovery (68%). CONCLUSIONS: Oral glucose solution administration when glycaemia was under 30 mg/dl in HIT produced a lower GH and cortisol response to insulin stimulus and a greater frequency of GH deficit diagnosis.     

The role of cortisol in the peripheral granulocyte response to insulin-induced hypoglycaemia in man

Peripheral blood leukocyte counts and plasma hormonal changes in response to acute insulin-induced hypoglycaemia were examined in 16 patients undergoing assessment of pituitary function. Eight subjects had a normal cortisol secretory response (Group 1), and 8 patients had definite hypopituitarism in whom the cortisol responses were deficient or absent (Group 2). An equivalent degree of hypoglycaemia was achieved in both groups. In Group 1a biphasic rise in leukocyte count occurred following hypoglycaemia, with an early rise in lymphocytes at 15 minutes after the acute hypoglycaemic reaction, and a later rise in granulocytes. A similar rise in lymphocytes was observed in Group 2, but the rise in the granulocyte count was attenuated, increasing from a basal value of 3.6 +/- 0.6 x 10(9) cells/L to a peak of 7.4 +/- 1.1 x 10(9) cells/L, compared with a peak of 11.7 +/- 1.2 x 10(9) cells/L in Group 1 (P less than 0.05). The usual increment in plasma cortisol in response to hypoglycaemia occurred in Group 1, but plasma cortisol did not rise in Group 2. A correlation was observed between the magnitude of the granulocyte rise and the increment in plasma cortisol in individual subjects (r = 0.64, P less than 0.02). This suggests that the rise in peripheral granulocytes following insulin-induced hypoglycaemia in man is mediated by cortisol released from the adrenal gland, following activation of the hypothalamic-pituitary-adrenal axis.     

Growth hormone,prolactin, and corticosteroid responses to insulin hypoglycaemia in alcoholics

Plasma growth hormone (GH), prolactin, and corticosteroid responses to insulin-induced hypoglycaemia were studied in 24 men with progressive alcoholism who had been abstinent for two to seven days. Ten normal healthy subjects (five men, five women) served as controls for comparing GH and prolactin responses, while cortisol responses were studied in a further six male controls. Blood samples were taken at intervals after an injection of soluble insulin (0·1 U/kg body weight). All patients developed adequate hypoglycaemia (blood glucose <2·2 mmol/l (<39·6 mg/100 ml)) and nine had impaired GH responses (peak concentration <10 mU/1). Prolactin concentrations fell or remained unchanged in nine patients, eight of whom also had impaired GH responses. In seven patients corticosteroid concentrations decreased from basal concentrations, and six of these patients had impaired GH responses. All three hormone responses were impaired in several patients, and significant correlations were found between the GH and prolactin responses at 45 and 60 minutes. GH response was not correlated with age, duration of drinking, duration of alcoholism, or admitted alcohol intake. GH responses were significantly lower in patients who had the most severe withdrawal symptoms. Our observations of impaired stress responses in some recently abstinent alcoholics may have important implications for the management of alcohol withdrawal syndrome.     

Hypothalamic-Pituitary Function in Depressive Illness: Insensitivity to Hypoglycaemia

The insulin tolerance test was performed in 16 severely depressed patients on admission to hospital and after treatment with electric convulsion therapy. The mean plasma cortisol response to hypoglycaemia was significantly impaired before treatment, particularly in the patients who also showed resistance to dexamethasone suppression. The results are consistent with hypothalamic-pituitary insensitivity to hypoglycaemia in these subjects.     

Comparison of Effects of Long-term Corticotrophin and Corticosteroid Treatment on Responses of Plasma Growth Hormone,ACTH, and Corticosteroid to Hypoglycaemia

The development of the highly sensitive cytochemical bioassay for ACTH has permitted the measurement of plasma ACTH levels during the insulin hypoglycaemia test (I.H.T.) in patients treated with corticosteroids and corticotrophin. The ACTH, corticosteroid, and growth hormone (GH) responses in the I.H.T. were measured in three groups of 12 rheumatoid arthritis patients. One group was receiving long-term corticotrophin treatment, the second was undergoing long-term corticosteroid treatment, and the third had never received systemic hormone therapy. The increments in plasma ACTH, corticosteroids, and GH were diminished in the corticosteroid-treated group, as were increments in plasma GH and ACTH in the corticotrophin-treated group; but in this group the corticosteroid increment was normal. Examination of the area under the curve of the ACTH response showed that the total amount of ACTH secreted was normal though the rate of secretion was reduced. In the corticosteroid-treated group both rate and total secretion were diminished.     

Short ACTH test in assessing hypothalamic-pituitary-adrenocortical function.

The adrenocortical response to the simple 30-minute ACTH stimulation test was compared with the hypothalamic-pituitary-adrenocortical (HPA) response to insulin-induced hypoglycaemia in 25 patients with various degrees of hypothalamic-pituitary malfunction. The correlations between the increase in plasma cortisol during insulin hypoglycaemia and that during ACTH stimulation (r = 0-66) and between peak plasma cortisol levels during the two tests (r = 0-90) were highly significant. Peak plasma cortisol levels in individual patients were similar on both tests, no patient showing any major discrepancy between the two test results. Thus the simple 30-minute ACTH stimulation test seems to be reliable in detecting imparied HPA function.     

Growth hormone releasing factor: comparison of two analogues and demonstration of hypothalamic defect in growth hormone release after radiotherapy.

Human pancreatic growth hormone releasing factor (hpGHRF(1-40] stimulates the release of growth hormone in normal subjects and some patients with growth hormone deficiency. A study comparing the shorter chain amidated analogue hpGHRF(1-29) with an equivalent dose of hpGHRF(1-40) in seven normal subjects showed no significant difference in growth hormone response between the two preparations. Six patients with prolactinomas were also tested; these patients had received megavoltage radiotherapy previously but had developed growth hormone deficiency as shown by insulin induced hypoglycaemia. In all six patients 200 micrograms hpGHRF(1-40) or hpGHRF(1-29)NH2 produced an increase in the serum growth hormone concentration. These data suggest that hpGHRF(1-29)NH2 may be useful for testing the readily releasable pool of growth hormone in the pituitary and that cases of hypothalamo-pituitary irradiation resulting in growth hormone deficiency may be due to failure of synthesis or delivery of endogenous GHRF from the hypothalamus to pituitary cells.     

Growth hormone,insulin, and prolactin secretion in anorexia nervosa and obesity during bromocriptine treatment.

We studied secretion of growth hormone (GH), insulin, and prolactin in eight women with anorexia nervosa and nine women with refractory obesity before and during treatment with bromocriptine, 10 mg/day. In the anorexic patients the raised plasma GH concentrations occurring during an oral glucose tolerance test fell significantly while on bromocriptine treatment, but there was no change in plasma insulin or blood glucose concentrations. In the obese patients, however, plasma GH concentrations remained low during the oral glucose tolerance test, and were not modified by bromocriptine. Blood glucose and plasma insulin concentrations were also unchanged. Plasma GH and plasma 11-hydroxycorticosteroid responses to insulin-induced hypoglycaemia were unaffected. Serum prolactin concentrations which were raised in five anorexic patients and marginally raised in two obese subjects, fell significantly in both groups during treatment. We observed no consistent weight changes in either groups.     

A case of asymptomatic cortisol producing adrenal adenoma.

We describe a man without the clinical findings of Cushing's syndrome, but who harbored an incidentally found cortisol-producing adrenal adenoma. On adrenal 131I-adsterol imaging, there was good uptake to the nodule, but no visualization of the contralateral adrenal. No abnormalities were found in the basal plasma cortisol, ACTH, urinary free cortisol and 17OHCS. However, dynamic hormone assessment revealed the existence of abnormal cortisol secretion: no suppression to dexamethasone, incomplete response to human corticotropin-releasing hormone, and lack of diurnal variation in plasma cortisol. Left adrenalectomy was performed with the diagnosis of cortisol-producing adrenal tumor. The pathological finding was an adrenal adenoma, and the perifusion of the excised tissues revealed a negligible response of the tumor tissue to ACTH though the residual normal cortex responded. Postoperative course was uneventful without replacement therapy with cortisol. It is suggested that the tumor autonomously produced a small amount of cortisol not only insufficient to provide clinical Cushing's syndrome, but also to provide typical suppression of hypothalamo-pituitary corticotroph-adrenal system.     

Effect of Feeding Inorganic Chromium on Growth Performance, Endocrine Variables, and Energy Metabolites in Winter-Exposed Buffalo Calves (Bubalus bubalis)

We investigated the effect of chromium (Cr) supplementation on the growth performance, energy metabolites, and hormonal variation in winter-exposed buffalo calves. Twenty-four female buffalo calves were randomly allotted to four dietary treatments (n?=?6) for a period of 120 days. Feeding regimen was the same in all the groups, except the animals in the four respective groups were additionally supplemented with 0.0, 0.5, 1.0, and 1.5 mg of Cr/kg DM in the form of CrCl₃.6H₂O. Calves were monitored daily for physiological variables and dry matter intake (DMI). Blood samples were collected at fortnightly intervals from each buffalo calves to measure concentrations of hormones (insulin, cortisol, and growth hormone), energy metabolites (glucose and non-esterified fatty acids), and plasma mineral levels. After 120 days of feeding trial, buffalo calves fed with Cr had lower (P?<?0.05) circulating plasma concentrations of glucose, insulin, and cortisol hormones, whereas plasma thyroid hormone and non-esterified fatty acids concentrations were found similar (P?>?0.05) among all the treatments. The results suggested that dietary Cr supplementation influenced plasma Cr levels without affecting the plasma concentrations of other trace minerals. However, physiological variables, nutrient intake, and growth performance of buffalo calves did not differ among all treatments (P?>?005). In summary, the current study showed that supplementation of Cr at the level of 1.0 and 1.5 mg of Cr/kg DMI was more effective in improving glucose utilization by increasing potency of insulin hormone and reducing concentration of cortisol hormone. Results also suggested that supplemental Cr also improves blood plasma Cr levels.     

The Effect of Acute Stress and Temperature on Plasma Cortisol and ion Concentrations and Growth of Lake Inari Arctic Charr, Salvelinus Alpinus

One year old, individually tagged Lake Inari Arctic charr, Salvelinus alpinus, were reared at three constant temperatures, 10.3°C, 14.1°C and 18.1°C, over four weeks. Blood samples were collected from a group of unstressed fish after the cultivation period at the same time as another group of fish were subjected to acute handling stress treatment (2min netting in air and 40min (± 20min) recovery period in water). Plasma cortisol, calcium, sodium, potassium and chloride concentrations were measured on both groups. To study the effect of minor daily temperature fluctuations on the stress response of Arctic charr, two additional daily fluctuating temperature (14 ± 1°C, 18 ± 1°C) treatments were established. The samples were taken in the same manner as those in the constant temperature treatments. Growth was fastest at 10.3–14.1°C and clearly lower at 18.1°C. Pre-stress plasma cortisol levels were low but increased slightly with increasing temperature. After stressor treatment, the cortisol concentrations of Arctic charr were clearly higher in all temperature treatments but there were no significant differences in plasma cortisol concentrations among temperatures. Plasma calcium levels increased during the stress treatment but temperature did not modulate this effect. The plasma potassium concentrations declined at 14.1–18.1°C after acute stress but the response was not affected by temperature within this range. The concentrations of sodium and chloride were unaffected by acute stress. Temperatures of 10.3–18.1°C and fluctuating temperature treatments had no influence on any plasma ion concentrations. Arctic charr were able to maintain the plasma ion concentrations in fresh water at 10.3–18.1°C and after acute stress treatment. Results indicate that the optimum temperature for growth of Arctic charr has little to do with the plasma ion concentrations or the ability to maintain those concentrations after short-term stress. The plasma cortisol responses further indicate that the optimum temperature for growth of Arctic charr is not related to the suppressed ability to react to an acute handling stressor. Temperature fluctuations did not cause significant differences in cortisol levels when compared with constant temperatures.     

Cortisol responses to the insulin hypoglycaemia test in children

AIM: To determine the timing of the peak cortisol response to the insulin hypoglycaemia (IH) test in children and to establish paediatric reference data. METHODS: We retrospectively reviewed all IH tests in a tertiary paediatric endocrine referral centre over a 6-year period. Inclusion criteria were age <16 years and adequate hypoglycaemia (glucose < or =2.0 mmol/l). Patients with an impaired hypothalamic-pituitary-adrenal axis or receiving glucocorticoid medication were excluded. Fifty-four subjects (35 males) met the criteria. Blood samples were collected at -30, 0, 20, 30, 60, 90, 120, and 150 min in relation to insulin bolus injection (0.15 U/kg) at 0 min. Glucose, cortisol, and growth hormone (GH) were measured in all samples. RESULTS: Peak cortisol and GH responses occurred by 90 min in all subjects. Peak cortisol was inversely correlated with age (rs -0.65, p<0.0001). The median (5th centile) peak cortisol value was 689 nmol/l (547 nmol/l) in children younger than 10 years as compared with 555 nmol/l (468 nmol/l) in those older than 10 years (p<0.0001). Peak cortisol was not related to peak GH (rs -0.20, p=0.15). CONCLUSIONS: Blood sampling in the IH test may be curtailed 90 min after injection. The peak cortisol response to IH is age related.     

Effect of an oral serotonin antagonist,ketanserin, on plasma ACTH concentrations in Nelson's syndrome.

A study was performed to see whether ketanserin, a serotonin antagonist, would reduce the raised concentrations of adrenocorticotrophic hormone (ACTH) in patients with Nelson''s syndrome. Six patients who had undergone bilateral adrenalectomy for Cushing''s disease and who had Nelson''s syndrome were given ketanserin 40 mg twice daily and placebo, for at least two months each, in a double blind crossover study. Ketanserin had no effect on ACTH concentrations. In healthy people serotonin seems to have a stimulatory role in the regulation of ACTH secretion, and the effect of ketanserin in reducing the ACTH response to hypoglycaemia suggested that it might prove useful in Nelson''s syndrome. These results show that it is not indicated in these patients.     

Growth, carcass composition and plasma growth hormone levels in cyclically fed rainbow trout

Growth, body composition and plasma growth hormone levels were recorded weekly for 24 weeks in rainbow trout Oncorhynchus mykiss . Underyearling rainbow trout were individually identified using coded tags and placed on either a cyclic feeding regime of 3 weeks of deprivation followed by 3 weeks of feeding or a daily feeding regime. No significant difference was found in standard length and mass among the cyclically fed and daily fed fish at the end of the experiment. For cyclically fed fish, the absolute specific growth rate and condition factor reached a maximum during the last week of refeeding. Cyclically fed fish had a significantly higher moisture and protein content and lower lipid levels relative to fish fed daily. Absolute mass and fat loss in the deprivation phase of the feeding cycle decreased in intensity with subsequent feeding cycles, indicating that the fish were acclimatizing to the feeding regime. It was proposed that this response was an adaptation against possible adverse effects in the adults ( e.g. locomotor performance, bone ossification rates, fat deposition rate, growth rate and age at sexual maturity). Plasma growth hormone concentrations were not affected by cyclic feeding indicating that variations in plasma growth hormone concentration are not the cause of compensatory growth in rainbow trout.