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)     

Exogenous somatostatin raises plasma insulin levels in patients with insulin-dependent diabetes mellitus

The effect of cyclic somatostatin on circulating insulin levels was studied in eight patients with insulin-dependent diabetes mellitus (IDDM). The study was performed after an overnight fast when their subcutaneous depots of insulin had been depleted during i.v. insulin substitution for 18 hours. A constant rate i.v. insulin infusion (0.4 mU/kg/min) was given for 240 min and somatostatin was co-infused between 60-120 min (100 micrograms/h) and 180-240 min (250 micrograms/h) respectively. Plasma insulin, blood glucose and hematocrit were measured at 15 min intervals. Hematocrit fell from 41.7 to 38.3% during the study period. Somatostatin increased the plasma insulin levels, corrected for the changes of hematocrit, by approximately 8% in the low dose (P less than 0.05) as well as in the high dose (P less than 0.05) period. It is concluded that somatostatin interferes with the clearance of insulin thereby increasing the circulating plasma insulin levels in IDDM patients without residual insulin secretion.     

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).     

Increase by somatostatin of the arginine induced rise in blood glucose in untreated insulin requiring diabetics.

We have demonstrated previously that cyclic somatostatin (GH-RIH) exerts a diabetogenic action in healthy subjects. To further examine the impact of this phenomenon studies of blood glucose (BG), immunoreactive insulin (IRI), glucagon (IRG) and growth hormone (GH) were performed in insulin requiring diabetics (n = 6) receiving i.v. arginine (0.5 g/kg) both in the absence and presence of i.v. GH-RIH (500 microgram/h). The infusion of GH-RIH-resulted in a persistent diminution in plasma IRI, IRG and GH. BG fell during i.v. GH-RIH during the initial 30 min and was below control values up to 45 min after initiation of i.v. arginine, but subsequently exceeded control levels (p less than 0.05 - less than 0.025). The excess rise in BG occurred in spite of suppression by somatostatin of the ariginine induced release of IRG, IRI and GH. A fall in BG was seen following cessation of i.v. GH-RIH and during a rebound of insulin release with glucagon levels remaining in the basal range. These findings indicate a diabetogenic action of somatostatin also in insulin requiring diabetics as long as some residual capacity for insulin release is retained.     

Improvement of impaired postoperative insulin action by bradykinin

The effect of bradykinin on insulin-stimulated glucose metabolism was studied in 5 operated patients using the euglycemic insulin clamp technique and the forearm catheter technique. Insulin infusion [1.0 mU/(kg b.w. X min)] raised plasma insulin levels up to 73 muU/ml. Euglycemia was maintained by a computerized glucose infusion rate, amounting to 2.9 mg/(kg b.w. X min). Addition of bradykinin [1.5 micrograms/(kg b.w. X h)] resulted in a significant increase of the glucose infusion rate [+ 1.0 mg/(kg b.w. X min)] indicating elevated whole body glucose uptake. This was related to an enhanced forearm glucose uptake [+ 1.16 mumol/(100 g X min)]. Forearm blood flow remained stable.     

Biological actions of peptide YY: effects on endocrine pancreas, pituitary-adrenal axis, and plasma catecholamine concentrations in the dog

The present study was designed to gather information on the biological activity of peptide YY (PYY) in conscious dogs. PYY was infused intravenously at a dose of 238 pmol/kg X h, and plasma concentrations of glucose, insulin, pancreatic polypeptide (PP), ACTH, cortisol and catecholamines (norepinephrine-NE; epinephrine-E; dopamine-DA) were subsequently measured. PYY significantly increased plasma insulin levels transiently without effect on plasma glucose, but decreased plasma PP levels during all infusion periods. PYY stimulated both plasma ACTH and cortisol secretion, and this action of PYY was also shared by PP, with PP being less potent in ACTH-cortisol release. PYY further elicited specific changes in plasma catecholamine concentrations, i.e. an increase of NE but not of E, which were in contrast to the effects of insulin-induced hypoglycemia. PP failed to alter plasma insulin and catecholamine concentrations. These results suggest that PYY can affect anterior pituitary hormone secretion, sympathetic nervous outflow and pancreatic endocrine activity in addition to its known actions on gastric and pancreatic secretion in the dog.     

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)     

Effect of hydrocortisone on ACTH, growth hormone, insulin and glucose in the blood of bilaterally adrenalectomized patients

This study is aimed at elucidating the mechanism of paradoxical rise in plasma ACTH levels in response to glucocorticoids, observed by several authors in bilaterally adrenalectomized patients with Cushing's disease. Six control subjects and fourteen patients bilaterally adrenalectomized for Cushing's disease were given a dose of 200 mg hydrocortisone sodium succinate by 3-5 mm i.v. injection. Plasma ACTH (in 6 patients), serum cortisol, growth hormone (GH) and insulin and blood glucose levels were estimated at 0, 30, 60, 90, and 120 minutes. The administration of hydrocortisone significantly suppressed plasma ACTH levels only at 60 min. In one case a slight rise in ACTH level during the test was observed. A significant fall in blood glucose levels was found only in the adrenalectomized patients. No significant changes in serum insulin and GH levels were noted. The possible mechanisms are discussed, especially the potential role of transient glucose deficiency in the pathophysiology of plasma ACTH increase in response to hydrocortisone in the bilaterally adrenalectomized patients.     

Role of calcium ion in acth-induced steroidogenesis in humans

In order to examine the role of calcium ion in ACTH-induced steroidogenesis in humans, we carried out infusion of a pharmacological dose of ACTH (4.2 micrograms/kg) and a physiological dose of ACTH (0.0084 microgram/kg) for 120 min, and infusion of dibutyryl cyclic AMP (DBcAMP) [0.33 mg/kg/min] for 20 min, in 22 normal subjects with or without verapamil treatment (360 mg/day, orally) for 5 days. The subjects were pretreated with 1.0 mg of dexamethasone and 5.0 mg of enalapril daily for 2 days before each infusion test to inhibit endogenous ACTH and angiotensin II. Following infusion of 0.0084 microgram/kg of ACTH, plasma levels of corticosterone (P less than 0.02) and cortisol (P less than 0.01) were significantly increased; with chronic verapamil treatment plasma levels of corticosterone (P less than 0.05) and cortisol (P less than 0.02) were significantly lower than those without verapamil. On the other hand, 4.2 micrograms/kg of ACTH for 120 min significantly increased the plasma levels of several steroid hormones, although there were no differences between the infusion with and without verapamil. Infusion of DBcAMP for 20 min significantly increased plasma levels of corticosterone (P less than 0.02) and cortisol (P less than 0.01), but verapamil did not affect the steroidogenic response to the DBcAMP infusion. The present results suggest that steroidogenesis induced by a physiological dose of ACTH differs from that after a pharmacological dose of ACTH or DBcAMP, and is mediated mainly by calcium ion as an intracellular messenger in man.     

The inhibitory action of corticotropin-releasing hormone on gonadotropin secretion in the ovariectomized rhesus monkey is not mediated by adrenocorticotropic hormone

Earlier observations in our laboratory indicated that i.v. infusion of human/rat corticotropin-releasing hormone (hCRH) suppresses pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in ovariectomized rhesus monkeys. Since cortisol secretion increased significantly as well, it was not possible to exclude the possibility that this inhibitory effect of hCRH on gonadotropins was related to the activation of the pituitary/adrenal axis. The purpose of the present study was to determine the role of pituitary/adrenal activation in the effect of hCRH on LH and FSH secretion. We compared the effects of 5-h i.v. infusions of hCRH (100 micrograms/h, n = 7) and of human adrenocorticotropic hormone (ACTH) (1-24) (5 micrograms/h, n = 3; 10 micrograms/h, n = 3, 20 micrograms/h, n = 3) to ovariectomized monkeys on LH, FSH, and cortisol secretion. As expected, during the 5-h ACTH infusions, cortisol levels increased by 176-215% of baseline control, an increase similar to that observed after CRH infusion (184%). However, in contrast to the inhibitory effect observed during the CRH infusion, LH and FSH continued to be released in a pulsatile fashion during the ACTH infusions, and no decreases in gonadotropin secretion were observed. The results indicated that increases in ACTH and cortisol did not affect LH and FSH secretion and allowed us to conclude that the rapid inhibitory effect of CRH on LH and FSH pulsatile release was not mediated by activation of the pituitary/adrenal axis.     

The development of beta-adrenergic mediated inhibition of growth hormone secretion in the ovine fetus

The ontogeny of the suppressive effect of the beta-adrenergic agonist, isoprenaline, on fetal growth hormone (GH) release was examined in 14 chronically-catheterized ovine fetuses. Isoprenaline was administered as an intravenous infusion over 1 h (200 micrograms/kg). In seven fetuses between 72 and 99 days of gestation, isoprenaline had no effect on fetal plasma GH concentrations. In seven older fetuses between 114 and 140 days of gestation, isoprenaline infusion suppressed (P less than 0.02) fetal GH release. No effect was observed in five saline-treated control fetuses (119-131 days). Propranolol (250 micrograms/kg i.v.) administered 5 min prior to the isoprenaline infusion to four fetuses (117-136 days) delayed (P less than 0.05) the onset of the suppressive effect of isoprenaline demonstrating that the action of isoprenaline was mediated by the beta-adrenergic receptor. Propranolol alone (n = 6) had no effect. These observations demonstrate that the potential for beta-adrenergic inhibition of fetal GH release differentiates after 100 days of gestation. Comparison with previous studies of the ontogenesis of the control of GH secretion suggests that the hypothalamic beta-adrenergic control of GH release differentiates with an intermediate time course compared to other potential neuroendocrine controls.     

Fasting and feeding variations of insulin requirements and insulin binding to erythrocytes at different times of the day in insulin dependent diabetics--assessed under the condition of glucose-controlled insulin infusion

Nine insulin-dependent diabetic patients were examined for insulin requirement, counterregulatory hormones, and receptor binding during their connection to glucose-controlled insulin infusion system. They were of 103% ideal body weight. A diet of 45% carbohydrate, 20% protein and 35% fat was divided into three meals and three snacks averaging the daily calorie intake of 1859 kcal. Following an equilibrating phase of 14 hours after the connection to the glucose-controlled insulin infusion system the blood samples were taken at 0800, 1200 and 1800. The insulin infusion rate increased at 0300 in the early morning from 0.128 mU/kg/min to 0.221 mU/kg/min (P less than 0.02). The postprandial insulin infusion rate jumped from 0.7 U/h (0700-0800) to 7.5 U/h (0800-0900). The calorie related and carbohydrate related insulin demands after breakfast were also highest and declined after lunch respectively (1.16 uU/kg/min kj vs. 0.61 uU/kg/min kj, P less than 0.05 and 236 mU/g CHO vs. 129 mU/g CHO and 143 mU/g CHO). Of the counterregulatory hormones the cortisol showed a significant diurnal rhythm to insulin demands. The insulin tracer binding was higher at 0800 before breakfast than that at 1200 before lunch (P less than 0.05). The increased binding could be better attributed to receptor concentration change than to affinity change. The cause of insulin relative insensitivity in the morning could be due to altered liver response to the cortisol peak in type 1 diabetics. The preserved variation of insulin binding in our patients might be referred to feeding.     

Effect of pancreastatin on pancreatic endocrine function in the conscious rat

We have studied the effects of pancreastatin on insulin and glucagon secretions in vivo in the conscious rat. Rats were prepared with a gastric fistula and with both external jugular veins cannulated. We found that an i.v. infusion of pancreastatin (1 and 10 nmol/kg/h) inhibited the plasma insulin response and increased the plasma glucose response to the intragastric infusion of glucose in a dose-dependent manner. Furthermore, the infusion of pancreastatin increased the plasma glucagon response to the i.v. infusion of arginine in a dose-dependent manner, and it inhibited the plasma insulin response. However, such an infusion of pancreastatin had no effect on the basal plasma glucose level, nor did it have any effect on plasma insulin and glucagon concentrations. Thus, it is suggested that in the rat, the newly discovered pancreastatin is a regulator of islet cell function.     

Adrenocorticotrophin responses to hypoxaemia in fetal sheep are sustained in the presence of naloxone.

We have examined the effects of fetal hypoxaemia, produced by reducing the percent oxygen in maternal inspired air, on fetal plasma concentrations of corticotrophin releasing hormone (CRH), adrenocorticotrophin (ACTH) and cortisol and determined the effects of an opioid receptor antagonist, naloxone on these responses. Hypoxaemia (fetal PO2, 15-18 mmHg) for 60 min provoked a significant (P < 0.05) increase in fetal plasma ACTH and cortisol concentrations at days 125-130 of pregnancy, but did not affect circulating CRH. There was no effect of naloxone administered either intravenously (1.25 mg bolus followed by a 2.5 mg/h continuous infusion for one hour; fetal body weight approximately 2.5 Kg) or via the lateral cerebral ventricle (50 micrograms bolus followed by a 100 micrograms/h infusion for one hour) on this pattern of ACTH and cortisol change nor on the lack of CRH response to hypoxaemia. We conclude that the increase in fetal ACTH and cortisol in response to acute hypoxaemia is not accompanied by an increase in systemic CRH concentrations, nor is the response dependent on short-term opioid regulation.     

Effect of synthetic ovine corticotropin-releasing factor on growth hormone secretion in patients with acromegaly

In a significant proportion of patients with acromegaly, a non-specific increase in plasma growth hormone (GH) has been recognized following administration of thyrotropin-releasing hormone (TRH) or luteinizing hormone-releasing hormone (LH-RH), probably due to the lack of the specificity of the receptor in their tumor cells. In this study, the effects of corticotropin-releasing factor (CRF), a newly isolated hypothalamic hormone, in addition to TRH and LH-RH, on plasma levels of GH and the other anterior pituitary hormones were evaluated in 6 patients with acromegaly. Synthetic ovine CRF (1.0 microgram/kg), TRH (500 micrograms) or LH-RH (100 micrograms) was given as an iv bolus injection, in the morning after an overnight fast. Blood specimens were taken before and after injection at intervals up to 120 min, and plasma GH, adrenocorticotropin (ACTH), thyrotropin, prolactin, luteinizing hormone, follicle-stimulating hormone and cortisol were assayed by radioimmunoassays. A non-specific rise in plasma GH was demonstrated following injection of TRH and LH-RH, in 5 of 6 and 2 of 5 patients, respectively. In all subjects, rapid rises were observed in both plasma ACTH (34.3 +/- 6.2 pg/ml at 0 min to 79.5 +/- 9.5 pg/ml at 30 min, mean +/- SEM) and cortisol level (9.1 +/- 1.3 micrograms/dl at 0 min to 23.4 +/- 1.2 micrograms/dl at 90 min). However, plasma levels of GH and the other anterior pituitary hormones did not change significantly after CRF injection. These results indicate that CRF specifically stimulates ACTH secretion and any non-specific response of GH to CRF appears to be an infrequent phenomenon in this disorder.     

Atrial natriuretic factor inhibits the CRH-stimulated secretion of ACTH and cortisol in man.

Corticotrophic secretion of ACTH is stimulated by corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), and suppressed by glucocorticoids. In vitro and preclinical studies suggest that atrial natriuretic factor (ANF) may be a peptidergic inhibitor of pituitary-adrenocortical activity. The aim of this study was to elucidate a possible role of ANF as a modulator of ACTH release in humans. A bolus injection of 100 micrograms human CRH (hCRH) during a 30 min intravenous infusion of 5 micrograms/min human alpha atrial natriuretic factor (h alpha ANF) was administered at 19:00 to six healthy male volunteers. In comparison to saline, a blunted CRH-stimulated secretion of ACTH (mean maximum plasma level +/- SD 45 min after hCRH: saline 46.2 +/- 14.2 pg/ml, h alpha ANF 34.6 +/- 13.8 pg/ml, p-value = 0.007) and a delayed rise (10 min) in cortisol were detected. The maximum plasma cortisol levels remained nearly unchanged between saline and h alpha ANF administration (mean maximum plasma level +/- SD 60 min after hCRH: saline 182 +/- 26 ng/ml, h alpha ANF 166 +/- 54 ng/ml). No effects of h alpha ANF on basal cortisol levels were observed; in contrast, basal ACTH plasma levels were slightly reduced. Basal blood pressure and heart rate remained unaffected. In the control experiment, infusion of 3 IU AVP in the same experimental paradigm increased basal and stimulated ACTH and cortisol levels significantly in comparison to saline. These observations suggest that intravenously administered haANF inhibits the CRH-stimulated release of ACTH in man.     

Responses of plasma adrenocorticotropin and cortisol to intravenous injection of synthetic ovine corticotropin releasing factor in the morning and early evening in normal human subjects

This study was designed to compare the responsiveness of adrenocorticotropin (ACTH) and cortisol secretion to corticotropin-releasing factor (CRF) in the morning and early evening in normal human subjects. Synthetic ovine CRF (1.0 micrograms/kg) or normal saline, was administered as an i.v. bolus injection to six normal males at 900 h and 1700 h. Blood samples were obtained before and 15, 30, 60, 90 and 120 min after CRF or saline injection. Significant increases in plasma ACTH and cortisol levels were observed in all subjects at the both time of testing after CRF injection. The net increments in the areas under the concentration curve (areas in the CRF experiment minus those in the saline control experiment) were not statistically different for both ACTH (mean +/- SEM: 41.0 +/- 10.6 pg/ml h in the morning: 51.1 +/- 8.9 pg/ml h in the evening) and cortisol (mean +/- SEM: 28.5 +/- 5.0 micrograms/dl h in the morning; 36.2 +/- 4.0 micrograms/dl h in the evening). Also no significant difference was observed in net increment, peak level and the ratio of peak level to the basal level of ACTH and cortisol after CRF injection. There were no appreciable changes in plasma concentrations of growth hormone, thyroid-stimulating hormone or prolactin, although slight but statistically significant rises in plasma levels of luteinizing hormone and follicle-stimulating hormone were observed. These results suggest that there is no significant difference in responsiveness of the pituitary-adrenal axis to CRF in the morning (900 h) and early evening (1700 h), and thus the time of day will not necessarily have to be considered when CRF is used between these times in a clinical test to evaluate pituitary ACTH reserve.     

Insulin dependence of the actions of growth hormone and somatostatin on splanchnic biogenic amines of the dog

It is known from studies previously conducted in this laboratory that an iv injection of ovine growth hormone (GH, 100 micrograms/kg BW) or an equimolar amount of somatostatin (SRIF, 7.5 micrograms/kg BW), given to normal conscious dogs into a saphenous vein, leads to a significant increase in hepatic portal plasma serotonin and a simultaneous decrease in the concentrations of dopamine, norepinephrine and epinephrine. The changes take place within 12 minutes after the injection and are observed only in the portal circulation. The purpose of the present experiment was to investigate whether or not similar results could be obtained in diabetic animals. Mongrel dogs were rendered diabetic by surgical pancreatectomy and fitted with an indwelling hepatic portal catheter. Radioenzymatic methods were employed for quantitative measurements of plasma free serotonin and catecholamines. No response was noted when the same type of experiments as those conducted in normal dogs were now carried out in trained, fully conscious totally pancreatectomized dogs deprived of exogenous insulin supply. When the same animals were given an injection into a peripheral vein of 50 mU/kg BW regular crystalline insulin (a small dose that affected neither plasma glucose nor biogenic amine levels) 10 minutes prior to the administration of the other hormones, the usual response to both GH and SRIF was restored, i.e. the data were comparable to those of normal dogs. It is concluded that the GH/SRIF effect on gut biogenic amines is insulin dependent.     

Nitric oxide decreases insulin resistance induced by high-fructose feeding.

The effect of nitric oxide (NO) on insulin resistance was studied in high-fructose-fed rats. A sequential hyperinsulinemic euglycemic clamp procedure was employed (insulin infusion rates: 3 and 30 mU/kg BW/min) in 12 high-fructose-fed rats and 12 chow-fed rats while awake. Half of the high-fructose-fed and the chow-fed rats, respectively, were continuously given sodium nitroprusside (SNP, 3 ng/kg BW/min) during the clamp study. Blood glucose was clamped at the fasting level in each rat. Plasma insulin levels during the 3 and 30 mU/kg BW/min insulin infusions were 30 and 400 microU/ml, respectively. Metabolic clearance rate of glucose (MCR) was regarded as an index of whole body insulin action. At both 3 and 30 mU/kg BW/min insulin infusions, high-fructose feeding showed a significant decrease in MCR compared with the chow-fed rats. However, decreased MCRs were stimulated by SNP administration and reached similar levels as the chow-fed rats. SNP infusion did not influence MCRs in the chow-fed rats. Therefore it could be concluded that NO can improve insulin resistance induced by high-fructose feeding.     

Influence of cycloheximide on acute diabetogenic effects of S-carboxymethylated human growth hormone in obese (ob/ob) mice

Acute treatment of ob/ob mice with S-carboxymethylated hGH (RCM-hGH), a diabetogenic derivative of GH which lacks significant insulin-like and growth-promoting activities, results in an increase in fasting plasma insulin and blood glucose levels and enhanced peripheral tissue insulin resistance. Plasma insulin level increases within 3 h after RCM-hGH is administered, whereas increased blood glucose concentration and enhanced peripheral tissue insulin resistance became evident 6 h after the hormone derivative is given. The lag period seen in the manifestation of these diabetogenic effects of RCM-hGH is consistent with the time required for gene expression. Therefore, the present study was undertaken to determine whether the above acute responses to the diabetogenic action of RCM-hGH would be expressed in ob/ob mice in which protein synthesis was blocked with cycloheximide. Female ob/ob mice were given either saline or cycloheximide (0.1 mg/g BW) ip and 1 h later were fasted and treated with either saline or 200 micrograms RCM-hGH ip. The mice were given a second injection of cycloheximide during the middle of the hormone treatment period to insure that protein synthesis remained blocked for the entire 6 h. In the animals not receiving cycloheximide, fasting plasma insulin level and blood glucose concentration were markedly elevated 6 h after the injection of RCM-hGH. Also, the GH derivative attenuated the ability of insulin added in vitro to stimulate glucose oxidation by adipose tissue segments isolated from the animals.(ABSTRACT TRUNCATED AT 250 WORDS)