Basal plasma aldosterone levels and tetracosactid-induced increase of aldosterone secretion in conscious male rabbits: lack of correlation with glucocorticosteroid levels

The adrenocortical secretory activity under basal conditions and after treatment with tetracosactid (1-24ACTH) has been investigated in chronically cannulated male rabbits. Basal plasma concentrations of glucocorticosteroids (0.74 micrograms/100 ml) and aldosterone (78 pg/ml) have been determined in a greater number of animals. No significant positive correlation between basal glucocorticosteroid and aldosterone plasma levels could be found. After intravenous injection of 2.5, 5.0, 10.0 and 20.0 micrograms/kg body weight tetracosactid glucocorticosteroid concentrations were significantly elevated between 40--100 min after administration; aldosterone release, on the other hand, was significantly increased only after injection of 10.0 or 20.0 micrograms/kg body weight tetracosactid between 20--60 min after injection. After administration of high tetracosactid doses glucocorticosteroid and aldosterone plasma concentrations were significantly correlated (10.0 micrograms/kg: r = 0.62; 20.0 micrograms/kg: r = 0.26). Because of the relative insensitivity of the zona glomerulosa cells to tetracosactid administered intravenously, it is concluded that ACTH is only of minor importance in the regulation of aldosterone secretion in the rabbit.     

Differences in cortisol, aldosterone and testosterone responses to ACTH 1-17 administered at two different times of day

The effects of 100 micrograms, i.m. of the analog ACTH 1-17 administered at 0800 and 1800 on the secretion of cortisol, aldosterone and testosterone have been studied in normal subjects: 8 male and 8 female. The group as a whole and the males had significantly greater absolute and percent increments in plasma cortisol after administration at 1800. In the females, there was only a greater percent increment in cortisol after the evening administration. The heptadecapeptide always significantly stimulated serum aldosterone, with no difference between the two times of administration. In the females, ACTH 1-17 significantly stimulated testosterone, with a more protracted secretion after the evening administration. In the males, there was always a significant testosterone decrease after the administration of the drug, with no difference between morning and evening. In conclusion, 100 micrograms i.m. of the analog ACTH 1-17 stimulates cortisol secretion more when given during the circadian nadir of plasma cortisol, but only in men. ACTH 1-17 increases testosterone in women and decreases it in men, whereas it seems to increase aldosterone secretion in both sexes.     

Alpha-melanocyte stimulating hormone increases plasma levels of glucagon and insulin in rabbits

Intravenous injections of 25 and 2.5 micrograms alpha-melanocyte stimulating hormone (alpha-MSH) increased plasma levels of glucagon, insulin and free fatty acids in fasted and fed rabbits. 45 micrograms beta-melanocyte stimulating hormone (beta-MSH) had similar effects, whereas 22 micrograms gamma-2-melanocyte stimulating hormone (gamma-MSH) was inactive. The alpha-MSH-induced increases in the plasma levels of glucagon, insulin and free fatty acids were not inhibited by alpha- or beta-adrenergic blocking drugs. The alpha-MSH-induced increases in the plasma levels of insulin were, however, augmented by phentolamine (an alpha-adrenergic receptor blocking drug). The plasma levels of glucose were increased by 25 micrograms alpha-MSH in fed rabbits, only, and were decreased by alpha-MSH during alpha-receptor blockade. The acute in vivo effects of alpha-MSH and beta-MSH on the plasma levels of glucagon, insulin and free fatty acids were rather similar to those previously reported for corticotropin (ACTH). It is possible that the 4-10 ACTH sequence, present in alpha-MSH, beta-MSH and ACTH, but not in gamma-MSH, is a message sequence for the observed effects. However, ORG 2766, a 4-9 ACTH analogue, was inactive. The mechanism by which alpha-MSH increased the plasma levels of glucagon and insulin in rabbits remains to be determined. It is possible, that the effects were mediated by both a central nervous action and a direct action on the endocrine pancreas.     

Corticosteroid,catecholamine and glucose plasma levels in rabbits after repeated exposure to a novel environment or administration of (1–24)ACTH or insulin

The responsiveness of the adrenal cortex and the sympathoadrenal-medullary system to stress factors and administration of (1–24) ACTH and insulin was studied in adult rabbits. In comparison to untreated animals, exposure to a novel environment for 10 min followed by artery puncture on 6 consecutive days elicited a moderate increase of corticosteroid (C), norepinephrine (NE) and epinephrine (E) plasma levels. Intramuscular injection of 50 μg/kg body weight (1–24) ACTH increased C, NE and E plasma levels. Saline injection resulted in elevated NE levels; C, E and glucose remained unchanged. After injection of 1.0 IU/kg body weight insulin C levels were higher than those found after exposure to a novel environment for 10mmin followed by artery puncture; similarly, NE and E were increased.In accordance with results obtained in the rat or mouse the sympathoadrenal-medullary system in the rabbit is stimulated by stress factors such as handling, artery puncture or injection of (1–24) ACTH or insulin. In contrast the adrenal cortex can be stimulated only to a certain extent by these manipulations. An increased activation of adrenal cortex cells occurs only after insulin, a maximum stimulation only after (1–24) ACTH administration.     

Interactions between oxytocin, glucagon and glucose in normal and streptozotocin-induced diabetic rats

Oxytocin has been suggested to have glucoregulatory functions in rats, man and other mammals. The hyperglycemic actions of oxytocin are believed to be mediated indirectly through changes in pancreatic function. The present study examined the interaction between glucose and oxytocin in normal and streptozotocin (STZ)-induced diabetic rats, under basal conditions and after injections of oxytocin. Plasma glucose and endogenous oxytocin levels were significantly correlated in cannulated lactating rats (r = 0.44, P less than 0.01). To test the hypothesis that oxytocin was acting to elevate plasma glucose, adult male rats were injected with 10 micrograms/kg oxytocin and killed 60 min later. Oxytocin increased plasma glucose from 6.1 +/- 0.1 to 6.8 +/- 0.2 mM (P less than 0.05), and glucagon from 179 +/- 12 to 259 +/- 32 pg/ml (P less than 0.01, n = 18). There was no significant effect of oxytocin on plasma insulin, although the levels were increased by 30%. A lower dose (1 microgram/kg) of oxytocin had no significant effect on plasma glucose or glucagon. To eliminate putative local inhibitory effects of insulin on glucagon secretion, male rats were made diabetic by i.p. injection of 100 mg/kg STZ, which increased glucose to greater than 18 mM and glucagon to 249 +/- 25 pg/ml (P less than 0.05). In these rats, 10 micrograms/kg oxytocin failed to further increase plasma glucose, but caused a much greater increase in glucagon (to 828 +/- 248 pg/ml) and also increased plasma ACTH. A specific oxytocin analog, Thr4,Gly7-oxytocin, mimicked the effect of oxytocin on glucagon secretion in diabetic rats. The lower dose of oxytocin also increased glucagon levels (to 1300 +/- 250 pg/ml), but the effect was not significant. A 3 h i.v. infusion of 1 nmol/kg per h oxytocin in conscious male rats significantly increased glucagon levels by 30 min in normal and STZ-rats; levels returned to baseline by 30 min after stopping the infusion. Plasma glucose increased in the normal, but not STZ-rats. The relative magnitude of the increase in glucagon was identical for normal and diabetic rats, but the absolute levels of glucagon during the infusion were twice as high in the diabetics. To test whether hypoglycemia could elevate plasma levels of oxytocin, male rats were injected i.p. with insulin and killed from 15-180 min later. Plasma glucose levels dropped to less than 2.5 mM by 15 min. Oxytocin levels increased by 150-200% at 30 min; however, the effect was not statistically significant.(ABSTRACT TRUNCATED AT 400 WORDS)     

Hyperglycemic effect of high doses of dobutamine in the rat: studies of insulin and glucagon secretion

The influence of dobutamine on glucoregulation has been assessed in the rat during and after an intravenous infusion given at the following doses: 0, 0.1, 1.0, 10, 100, and 1000 micrograms X kg-1 X min-1. Plasma glucose, insulin, and glucagon levels were measured at 15-min intervals in unanesthetized previously cannulated rats. Basal glucose levels were preserved with the less than or equal to 10 micrograms X kg-1 X min-1 doses. At the greater than or equal to 100 micrograms X kg-1 X min-1 doses, a marked hyperglycemic effect was observed, partly attributable to some inhibitory effect of dobutamine on glucose-induced insulin secretion and to its stimulatory effect on glucagon secretion. Such data suggest that dobutamine may disturb the normal glucose homeostasis, particularly in situations of deficient insulin reserve.     

Plasma glucocorticosteroid and aldosterone levels during physiological and stress conditions in rabbits. II. adult animals

The pattern of adrenal steroid secretion under basal and stress conditions and the response to tetracosactid (20.0 micrograms/kg body weight) were studied in adult male rabbits. In animals repeatedly stressed by artery puncture, plasma glucocorticosteroid levels were slightly higher than those found in unstressed control animals. The combined stress of repeated exposure to ether vapor for 60 sec, followed by artery puncture, significantly stimulated glucocorticosteroid release, concentrations progressively increasing with the number of ether exposures applied. A much faster and more pronounced stimulation of glucocorticosteroid release was seen in animals treated with 20.0 micrograms/kg body weight tetracosactid. Plasma aldosterone levels in animals stressed by artery puncture were higher, although not significantly, than those of unstressed control animals. Repeated exposure to ether vapor for 60 sec, followed by artery puncture, on the other hand slightly decreased plasma aldosterone concentrations. A strong stimulation of aldosterone release at 20--60 min after injection could be elicited only by intravenous administration of 20.0 micrograms/kg body weight tetracosactid. Because of the insensitivity of the zona glomerulosa cells to increased ACTH levels under stress conditions, it is concluded that ACTH is only of minor importance both under basal and stress conditions in the regulation of aldosterone secretion in the rabbit.     

The effect of MSH/ACTH 4-10 on delayed response performance and post-test locomotor activity in rats

Delayed response performance was measured in male, Long-Evans rats 1 hr after IP administration of various doses of MSH/ACTH 4-10 or control in a Hunter delayed reaction apparatus. Additional treatments consisting of naloxone 500 micrograms/kg (IP) and naloxone 500 micrograms/kg in conjunction with MSH/ACTH 4-10 95 micrograms/kg were also administered. Directly after delayed response performance was assessed, gross locomotor activity was determined. MSH/ACTH 4-10, at a dose of 95 micrograms/kg, significantly enhanced retention of a visual stimulus, while MSH/ACTH 4-10, at doses of 195 and 285 micrograms/kg, significantly impaired delayed response performance. Naloxone treatment resulted in significantly impaired delayed response performance when compared to control. However, naloxone plus MSH/ACTH 4-10 treatment failed to produce a significant difference from control in the delayed response performance paradigm. In post-test locomotor activity determination, an apparent dose-response existed for MSH/ACTH 4-10 with the two highest doses (190 and 285 micrograms/kg) resulting in significantly increased locomotor activity. The observed delayed response performance data support theories implicating MSH/ACTH peptides in attentional processes involving visual stimuli. The fact that large doses of MSH/ACTH 4-10 disrupt delayed response performance while increasing post-test activity suggest that an optimum level of effect caused by the MSH/ACTH peptide exists in this paradigm.     

The time-course of ACTH stimulation of cortisol synthesis by the immature ovine foetal adrenal gland.

The aim of this study was to establish the time-course of foetal adrenal gland activation by ACTH at a period of intra-uterine development during which adrenal function is minimal (100-120 days of gestation). Blood samples for cortisol analysis were collected at 6-h intervals during the 24 h ACTH (0.05, 0.5 and 5.0 micrograms/h) infusion and during the subsequent 24-h period following cessation of the infusion. Plasma cortisol concentrations were measured using a newly developed radioimmunoassay, whose sensitivity was found to be comparable to that of the validated double-isotope dilution derivative method. There was a significant increase in foetal plasma cortisol concentration, from 3.9 +/- 1 to 17.8 +/- 1.9 nmol/l, within 12 h of commencement of the 2 higher doses of ACTH. Values are mean +/- SEM; n = 5. Following termination of the infusion, cortisol levels fell significantly by the first 6 h, returning to basal levels thereafter. An increase in plasma ACTH from 4.6 +/- 0.6 to 8.4 +/- 1.0 pmol/l was sufficient to initiate a significant increase in cortisol production. The results suggest that the normal low values of cortisol at this period of gestation result from inadequate endogenous ACTH production at this stage.     

Pharmacological doses of oxytocin affect plasma hormone levels modulating glucose homeostasis in normal man

Pharmacological doses of oxytocin administered in basal conditions evoked a rapid surge in plasma glucose and glucagon levels followed by a later increase in plasma insulin and adrenaline levels. The effects of oxytocin on plasma glucagon and adrenaline levels were potentiated by hypoglycemia. When the endogenous pancreas secretion was suppressed by cyclic somatostatin (150 micrograms/h) and exogenous glucagon (3.5 micrograms/h) and insulin (0.2 mU/kg.min) were both replaced, oxytocin (0.2 U/min) evoked a transient but significant increase in plasma glucose levels suppressing the glucose infusion rate (GIR) in the first 60 min. On the contrary at higher insulin infusion rate (0.6 mU/kg.min) plasma glucose levels and GIR remained unaffected throughout the study. Oxytocin seems also to potentiate glucose-induced insulin secretion as evidenced by hyperglycemic glucose clamp. In conclusion, pharmacological doses of oxytocin seem to exert a prevalent hyperglycemic effect by a combined action at the liver site (as glycogenolytic agent) and at the endocrine pancreas (as a stimulatory agent of A cell secretion).     

Effects of synthetic ovine corticotropin-releasing factor (CRF) on plasma ACTH and cortisol in 31 normal human males

Responses of plasma ACTH and cortisol to corticotropin-releasing factor (CRF) were evaluated in 31 normal human males. 1.0 micrograms/ks of sterilized synthetic ovine CRF was administered to the subjects, aged 19 to 53 yr and weighing 50 to 78 kg, at between 9:30 a.m. and 10:30 a.m. as an intravenous bolus injection after an overnight fast. Blood specimens were drawn before and 15, 30, 60, 90 and 120 min after injection for later determination of plasma ACTH and cortisol concentrations by radioimmunoassays. Plasma ACTH and cortisol levels for all subjects rose significantly (p less than 0.001) from the basal level (mean +/- SEM, 26.8 +/- 4.5 pg/ml and 12.6 +/- 0.9 micrograms/dl) to peak levels (58.4 +/- 5.5 pg/ml and 22.9 +/- 1.0 micrograms/dl) at 30 min and at 60 min, respectively. Although the plasma concentrations of ACTH and cortisol thereafter declined gradually, the levels at 120 min (43.4 +/- 5.2 pg/ml and 18.9 +/- 0.9 micrograms/ml, respectively) were still significantly higher than the basal levels (p less than 0.001). Significant inverse correlations were observed between the basal levels of each hormone and the ratio of the peak level to the basal level (p less than 0.01), and the increases in plasma ACTH and cortisol concentrations were either not significant or much smaller for the individuals in whom the basal levels were higher than 65 pg/ml and 17.0 micrograms/dl, respectively. No serious subjective symptom was observed during the experimental period in any of the subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

An improved dispersed adrenal cell assay for corticotropin in rat plasma

The present study was designed to improve the dispersed adrenal cell technique for determining adrenocorticotrophic hormone (ACTH) concentrations in small amounts of rat plasma. Priming with ACTH, incubation with methyl-isobutylxanthine, or dexamethasone pre-treatment were employed as modifications. Of these, only dexamethasone pre-treatment increased the sensitivity of the assay. The adrenal fragments obtained from 10-12 adult male rats pre-treated with dexamethasone (100 micrograms/kg B.W.) one hour before sacrifice, were digested with collagenase and deoxyribonuclease solution for 30 minutes. The dispersed cells were collected by centrifugation and resuspended in Krebs-Ringer bicarbonate buffer containing 0.2% glucose and 0.5% bovine serum albumin. Aliquots of cell suspension (3-4 X 10(4)/tube) were incubated with various doses of ACTH1-24 or the eluate of plasma samples at 37 degrees C for 2 hours in an atmosphere of 95% O2/5% CO2 in a Dubnoff shaker. The quantity of corticosterone produced was measured fluorimetrically. The assay is precise (lambda = 0.06), extremely sensitive (10 fg/tube), and convenient. One skilled technician can handle 15 to 20 plasma samples per day using 10 rats as the source of assay cells. ACTH can be measured in as little as 10-50 microliters of eluate.     

Effects of a long-acting somatostatin analogue on pituitary-adrenocortical secretion in normal human subjects

A potent and long-acting somatostatin analogue, SMS 201-995 (SMS) is currently employed for the treatment of various diseases with hypersecretion of hormones such as acromegaly and gastrinoma. The suppressive effects of SMS are also reported on the other pituitary and gastrointestinal hormones. The corticotropic-adrenocortical axis is a crucial hormonal complex in maintaining normal activity and life itself. In this study, the effects of SMS on corticotropic-adrenocortical functions were studied, since the effects of SMS on this hormonal axis are not well established. Seven normal males received a sc injection of 100 micrograms SMS or placebo at 0830 h and 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) intravenously (SMS-hCRH study). Five of the 7 subjects were given an injection of a synthetic (1-24) ACTH (250 micrograms or 63 micrograms) at 0900 h after 100 micrograms SMS or a placebo at 0830 h (SMS-ACTH study). Blood samples were drawn at -30, 0, 15, 30, 60, 90 and 120 min after the hCRH injection for the determination of ACTH and cortisol in the SMS-hCRH study, and cortisol and aldosterone in the SMS-ACTH study. Although significant rises in plasma ACTH and cortisol levels were observed regardless of the preinjection of SMS, their responses to hCRH were significantly lower with the pretreatment with SMS than without SMS. A significant increase in plasma cortisol and aldosterone was observed in response to synthetic ACTH with both ACTH alone and the combined administration of SMS and ACTH, at either dose of ACTH. However, no significant difference in cortisol and aldosterone secretion was detected with and without SMS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Feedback suppression of ACTH secretion by cortisol in dogs: lags after large signals equal those following very small signals

Previously, low stepwise infusions of cortisol in resting adrenalectomized dogs (plateaux less than or equal to 6 micrograms/dL) were shown to reduce ACTH secretion only after 20 min. In the present study, large, steep-sloped cortisol signals were used to try to evoke faster feedback. Adrenalectomized male mongrel dogs were maintained on exogenous steroids until 48 h before the experiment. Of the 23 experiments on 15 dogs (under light pentobarbital anesthesia), 12 were on resting dogs, 7 on dogs stressed by variable insulin infusion (keeping plasma glucose at 18-40 mg/dL), and 4 stressed as above but with 4 h of low cortisol infusion (plasma congruent to 5 micrograms/dL) before applying the feedback signal. After a 50-min control period, a 30-min feedback period was initiated by one of two i.v. cortisol signals: (a) injection of 0.3 mg/kg or (b) infusion of 46 micrograms kg-1 min-1. Both raised plasma cortisol above physiological limits (within 2 and 6 min, respectively). In each experiment, 23 timed venous blood samples were assayed for plasma ACTH and cortisol. ACTH secretion rates were calculated continuously using a validated single-compartment method. Results from both types of cortisol signals were indistinguishable, and were thus pooled. In the unstressed dogs, control-period ACTH secretion of 0.97 +/- 0.12 mU kg-1 min-1 showed no significant decline due to the feedback signal for 20.3 +/- 1.4 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological responses to low dose infusions of atrial peptide in conscious dogs

Mongrel dogs prepared with chronic catheters in their femoral artery and vein and urinary bladder received 60 minute infusions of atrial peptide ranging from 5 to 100 ng/kg/min. Infusion of atrial peptides caused dose dependent increases in plasma atrial peptide concentration with doses of 25 ng/kg/min or less increasing plasma concentrations to levels observed in normal animals during stimulation of endogenous atrial peptide secretion. Atrial peptide infusion at doses of 10 ng/kg/min and above caused significant decreases in mean arterial pressure which were not accompanied by statistically significant changes in heart rate. Atrial peptide infusion at doses of 25 ng/kg/min and above increased urinary sodium excretion and urine flow rate. Atrial peptide infusion was without effect on plasma vasopressin, ACTH and corticosterone concentrations. However, atrial peptide infusion resulted in dose dependent decreases in plasma aldosterone concentration and plasma renin activity, but the decreases were only significant with the high physiologic (25 ng/kg/min) and pharmacologic doses (50 & 100 ng/kg/min). These data show that atrial peptide infusions in conscious dogs have minimal effects when infused in small doses that mimic endogenous atrial peptide release. At higher doses, significant effects on the cardiovascular, renal and endocrine systems can be observed but their physiological significance is unclear.     

In vitro effect of insulin and insulin-like growth factor-I on cell multiplication and adrenocorticotropin responsiveness of fetal adrenal cells

The present study examined the effects of both insulin and insulin-like growth factor-I (IGF-I) on cell division and specific functions of cultured adrenocortical cells from 100- to 122-day-old ovine fetuses. When culture was performed in a serum-free medium containing transferrin and ascorbic acid, the number of cells increased only slightly (1.2-fold) over a 4-day period. Addition of insulin or IGF-I in the culture medium enhanced the number of cells counted on Day 5. The effect of both peptides was dose-dependent, but 10 ng/ml IGF-I was as potent as 10 micrograms/ml insulin. The acute cyclic adenosine 3',5'-monophosphate (cAMP) and steroidogenic responses to adrenocorticotropin (ACTH1-24) decreased in fetal cells cultured in the absence of insulin or ACTH. Insulin at micromolar concentrations not only prevented this decrease but enhanced the acute ACTH1-24-induced cAMP output on Day 5 over that observed on Day 2. Treatment of fetal cells for 4 days with increasing concentrations of insulin or IGF-I enhanced the acute cAMP and steroidogenic responses (3- to 4-fold) to ACTH1-24 over that of control cells. The ED50 of IGF-I was about 3 ng/ml (congruent to 0.4 nM) whereas that of insulin was about 10 ng/ml (1.7 nM). However, a second plateau was apparent at concentrations of insulin above 1 microgram/ml. The acute cholera toxin stimulation of cAMP production of cells cultured in the absence of insulin or ACTH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased sensitivity to somatostatin in obese Zucker rats

The release of somatostatin from the pancreas and stomach following the ingestion of a meal and its increase in the peripheral circulation elicits an attenuation of postprandial hormone secretion such as insulin, pancreatic polypeptide and gastrin and retards the rate at which nutrients enter the circulation. Reduced tissue somatostatin content and/or an attenuated somatostatin release is associated with hyperinsulinism and obesity in certain animal models. In the obese Zucker rat, however, tissue somatostatin levels are increased and therefore the present study was designed to determine the effect of synthetic somatostatin on basal and postprandial arterial insulin levels in obese and lean Zucker rats. Synthetic somatostatin was infused at doses of 0.25, 0.5, 1 and 5 ng/kg X min before and after the intragastric instillation of a liver extract/sucrose test meal. In the obese rats somatostatin at a dose of 5 ng/kg X min reduced basal plasma insulin levels significantly, whereas no effect of somatostatin was observed on basal insulin levels in the lean animals at all doses employed. The integrated postprandial insulin response was reduced during 0.25, 0.5, 1 and 5 ng/kg X min somatostatin in the obese animals, whereas only 0.5 ng/kg X min and higher doses had an inhibitory effect in the lean rats. The degree of inhibition in relation to the postprandial insulin response during saline infusions was 35-230% in the obese and 30-100% in the lean Zucker rats within the range of somatostatin infusions employed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Demonstration of a dawn phenomenon in normal adolescents

To ascertain whether the dawn phenomenon occurs in normal adolescents and, if so, to determine its mechanism, we measured nocturnal plasma glucose, insulin, glucagon, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH) levels between 01.00 and 08.00 h in 10 healthy adolescents. The prehepatic insulin secretion rate was calculated based on C peptide levels. The metabolic clearance rate of insulin (MCRI) was calculated as the ratio of mean insulin secretion rate to mean insulin concentration. There was no change in plasma glucose, insulin, and glucagon between 01.00-04.00 and 05.00-08.00 h (paired t test). The MCRI was higher at 05.00-08.00 h compared to 01.00-04.00 h (9.30 +/- 1.50 vs. 4.87 +/- 1.11 ml.kg-1.min-1; p = 0.008). The prehepatic insulin secretion increased at 05.00-08.00 h relative to 01.00-04.00 h (1.1 +/- 0.2 vs. 0.6 +/- 0.1 pmol.kg-1.min-1; p = 0.013). Similarly, cortisol and ACTH levels were higher at 05.00-08.00 versus 01.00-04.00 h (323 +/- 33 vs. 102 +/- 22 nmol/l, p less than 0.001; 3.6 +/- 0.5 vs. 1.8 +/- 0.4 pmol/l, p = 0.006, respectively). Growth hormone was higher at 01.00-04.00 versus 05.00-08.00 h (7.6 +/- 1.2 and 3.0 +/- 0.9 microgram/l; p = 0.019). ACTH correlated with MCRI (r = 0.66; p = 0.002) and prehepatic insulin secretion (r = 0.75; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential modulation of ACTH-stimulated cortisol and androstenedione secretion by insulin

Results of previous clinical studies suggested counter regulatory actions between insulin and DHEA(S). The present studies were performed using primary monolayer cultures of bovine fasciculata-reticularis cells to test the hypothesis that insulin directly affects adrenal androgen secretion. Although having no independent effect, insulin exhibited complex time- and concentration-specific actions on ACTH-stimulated secretion of both C21 (cortisol) and C19 (androstenedione) corticosteroids. In the presence of low concentrations (0.05-0.1 nM) of ACTH, cortisol secretion during a 2 h incubation was about 2-fold greater in the presence than in the absence of insulin (0.01-100 ng/ml). In the presence of a maximal concentration (10 nM) of ACTH, on the other hand, cortisol secretion was not affected by insulin at concentrations less than or equal to 0.1 ng/ml, but was decreased at higher insulin concentrations. ACTH-stimulated androstenedione secretion was not significantly affected by insulin during a short-term (2 h) incubation. During a prolonged (24 h) incubation, insulin produced a concentration-dependent inhibition of ACTH-stimulated cortisol secretion. At an insulin concentration of 100 ng/ml, ACTH (10 nM)-stimulated cortisol secretion declined to a level only 30% of that produced by ACTH alone. In contrast, insulin exhibited biphasic effects on the secretion of androstenedione by cells maintained in the presence of ACTH for 24 h; an effect that was most dramatic in the presence of a maximal concentration of ACTH. At an insulin concentration of 0.1 ng/ml, androstenedione secretion by cells maintained in the presence of 10 nM ACTH was increased approximately 2.5-fold. At higher concentrations of insulin, ACTH-stimulated androstenedione secretion was inhibited to an extent comparable to that in cortisol secretion. The effects of insulin on ACTH-stimulated cortisol and androstenedione secretion could not be accounted for by changes in steroid degradation or a loss in 11 beta-hydroxylase activity. These results indicate that insulin interacts with ACTH to modulate the secretion of both C21 and C19 corticosteroids and that physiological concentrations (less than or equal to 1 ng/ml) of insulin may have a long-term effect to enhance selectively adrenal androgen secretion. These data are consistent with a servo mechanism between insulin and DHEA(S) in vivo and indicate that the correlations observed clinically result, at least in part, from a direct action of insulin to modulate the rate of adrenal androgen production.     

Diabetogenic action of GH and cortisol in insulin-dependent diabetes mellitus. Aspects of the mechanisms behind the Somogyi phenomenon

The effect on glucose homeostasis of a transient elevation of plasma growth hormone (GH) and cortisol was studied over 6 h in 14 male patients with insulin-dependent diabetes mellitus (IDDM) by using an i.v. somatostatin (100 micrograms/h) - insulin (0.4 mU/kg/min) glucose (3 mg/kg/min) - infusion test (SIGIT). GH (20 mU/kg) was given as a 60 min i.v. infusion during the initial SIGIT period raising the plasma GH level to about 40 micrograms/l, and returning to low basal within 3 h. ACTH (0.1 mg) was given as an i.v. bolus injection at the start of the SIGIT, resulting in plasma cortisol peak values of about 900 nmol/l within 2-3 h. GH raised blood glucose after a lag of 4 h while ACTH alone had no effect. However, ACTH added to GH enhanced the diabetogenic effect of GH. It is concluded that an episodic increase in circulating GH-cortisol, resembling the responses of these hormones to an insulin-induced hypoglycemia, exerts a diabetogenic effect in IDDM-patients not deprived of insulin. While GH is essential in this respect the diabetogenic effect of cortisol is evident only in conjunction with GH.