The effects of lead poisoning on various plasma constituents in the Canada goose.

Plasma glucose, free fatty acid and uric acid levels were measured in lead-poisoned Canada geese (Branta canadensis). Although plasma glucose levels were only slightly elevated, uric acid was significantly higher and free fatty acids were significantly lower. Altered plasma levels were attributed to increased protein catabolism and perhaps renal disfunction. Plasma level of growth hormone and prolactin was assessed by radioimmunoassay. Growth hormone remained unchanged while prolactin was unusually high. The increased prolactin levels may reflect an effort to stabilize free fatty acids.     

Carbohydrate metabolism in rats after partial or total isolation of the medial hypothalamus.

After medial hypothalamic deafferentation at complete (CD), frontal (FD), or frontolateral (FL) levels, at the same time with adrenocortical hormone determination, sensitivity to insulin and insulinemia were determined at a postoperative time, when adenohypophyseal hormonogenetic process concerned to ACTH and growth hormone, is reverted to the normal. The glucose assimilation coefficient (K) was followed weekly for a month postoperatively. Insulin sensitivity decreased after CD and increased after FD. FL and CD rats had significantly elevated plasma insulin level, despite normoglycemia. The changes recorded in plasma insulin level and sensitivity to insulin are attributed primarily to the CNS defect. After hypothalamic isolation, K is unchanged. This might point to the creation of new set point for hypo- and hyperglycemiating system, respectively. We concluded that the presence of nervous connections of the medial hypothalamus with surrounding nervous structures is necessary for a normal carbohydrate metabolism control.     

Hormonal and Metabolic Studies in Pheochromocytoma

One patient with benign and another with malignant pheochromocytoma have been studied in an attempt to elucidate the effect of increased catecholamines on the response of blood sugar, unesterified fatty acids, insulin and growth hormone to a glucose load. The presence of increased catecholamines in both patients appeared to produce increased fasting plasma unesterified fatty acid levels, carbohydrate intolerance and an unusual plasma growth hormone response to glucose. There was no interference with the normal decrease in plasma unesterified fatty acids after glucose ingestion. The malignant tumour, but not the benign one, was associated with low plasma insulin levels.After removal of the benign tumour the fasting unesterified fatty acid levels became normal. In addition, following glucose ingestion there appeared to be a more normal plasma insulin and growth hormone response and improved glucose tolerance. After removal of the primary malignant tumour it is noteworthy that the distant metastases secreted abnormal amounts of both adrenaline and noradrenaline.     

Growth hormone secretion during pregnancy: altered effects of growth hormone releasing factor and insulin-like growth factor-I in vitro

Growth hormone (GH) secretion is controlled by growth hormone releasing factor (GRF) but changes in the circulating level of this hormone are difficult to measure. Insulin-like growth factor (IGF-I) is a GH-dependent growth factor which significantly but slightly inhibits stimulated GH release in vitro. We have tested the effects of GRF and IGF-I on GH release in pregnancy, a state in which serum concentrations of GH are elevated and levels of IGF-I are lowered. We have found, in a system of acutely dispersed adenohypophysial cells prepared from pregnant (day 21-23) or control cycling female rats, that adenohypophysial cells from pregnant rats have an increased GH release with GRF. In contrast, IGF-I inhibition is similar but slightly smaller. These altered responses may result in elevated serum GH levels during pregnancy.     

Aged PROP1 deficient dwarf mice maintain ACTH production

Humans with PROP1 mutations have multiple pituitary hormone deficiencies (MPHD) that typically advance from growth insufficiency diagnosed in infancy to include more severe growth hormone (GH) deficiency and progressive reduction in other anterior pituitary hormones, eventually including adrenocorticotropic hormone (ACTH) deficiency and hypocortisolism. Congenital deficiencies of GH, prolactin, and thyroid stimulating hormone have been reported in the Prop1(null) (Prop1(-/-)) and the Ames dwarf (Prop1(df/df)) mouse models, but corticotroph and pituitary adrenal axis function have not been thoroughly investigated. Here we report that the C57BL6 background sensitizes mutants to a wasting phenotype that causes approximately one third to die precipitously between weaning and adulthood, while remaining homozygotes live with no signs of illness. The wasting phenotype is associated with severe hypoglycemia. Circulating ACTH and corticosterone levels are elevated in juvenile and aged Prop1 mutants, indicating activation of the pituitary-adrenal axis. Despite this, young adult Prop1 deficient mice are capable of responding to restraint stress with further elevation of ACTH and corticosterone. Low blood glucose, an expected side effect of GH deficiency, is likely responsible for the elevated corticosterone level. These studies suggest that the mouse model differs from the human patients who display progressive hormone loss and hypocortisolism.     

Calcium metabolism, serum thyroid-stimulating hormone, prolactin, and growth hormone in spontaneously hypercholesterolemic rats

We have shown previously that spontaneously hypercholesterolemic (SHC) rats exhibit abnormal bone metabolism with advanced bone resorption, which develops with age. In this study, we measured serum levels of growth hormone, thyroid-stimulating hormone, and prolactin in addition to several parameters of calcium metabolism and renal function in young (6-week) and old (24-week) SHC rats and compared these with age-matched Sprague-Dawley rats. In young SHC rats, urinary excretion of hydroxyproline and serum levels of calcium were significantly elevated and excretion of protein into urine and urea nitrogen in the serum were normal, suggesting that calcium metabolism was abnormal without kidney dysfunction at this age. Serum growth hormone and thyroid-stimulating hormone levels were markedly higher (20- to 30-fold and 4- to 5-fold, respectively) in young and old SHC rats, whereas serum prolactin levels were similar. A high level of serum thyroid-stimulating hormone was associated with elevated levels of thyroxine and triiodothyronine in young SHC rats, but not old ones. These results demonstrate that the rat exhibits abnormalities in endocrine function as well as calcium metabolism preceding the occurrence of renal dysfunction.     

Growth hormone and carbohydrate intolerance in cirrhosis

Patients with cirrhosis of the liver often have insulin resistance and elevated circulating growth hormone levels. This study was undertaken (a) to evaluate glucose intolerance, insulin resistance and abnormal growth hormone secretion and (b) to determine if GH suppression improves insulin resistance. Glucose tolerance tests (GTT), intravenous insulin tolerance tests (IVITT), arginine stimulation tests (AST) and glucose clamp studies before and during GH suppression with somatostatin were performed in a group of patients with alcohol-induced liver cirrhosis. During GTT cirrhotic subjects had a 2-hour plasma glucose of 200 +/- 9.8 ng/dl (N = 14) compared to 128 +/- 8.0 ng/dl in normal controls (N = 15), P less than 0.001. Basal GH was elevated in cirrhotic patients and in response to arginine stimulation reached a peak of 17.0 +/- 5.4 ng/ml (N = 7), compared to a peak of 11.3 +/- 1.8 ng/ml in 5 normal controls (P = NS). During IVITT patients with cirrhosis had a glucose nadir of 60.0 +/- 4.0 mg/dl (N = 9), compared to 29.0 +/- 7.0 mg/dl in controls (N = 5), P less than 0.001. Peak GH levels during IVITT were not significantly different in cirrhotics and controls. Glucose utilization rates in 4 patients with cirrhosis of the liver before somatostatin mediated GH suppression was 3.1 +/- 0.5 mg/kg/min and 6.5 +/- 1.5 mg/kg/min during somatostatin infusion, P less than 0.025. We conclude that patients with alcohol induced cirrhosis have sustained GH elevations resulting in insulin resistance which improves after GH suppression.     

The effect of vasotocin on plasma glucose, free fatty acids and growth hormone in the frog, Rana catesbeiana

Injections of arginine vasotocin into bullfrogs had no effect on plasma glucose after 30 min. but caused hyperplycemia after 120 min. Plasma levels of growth hormone were elevated earlier (30 min.) and returned to control levels after 120 min. Plasma free fatty acids were unaltered following vasotocin administration. It is suggested that the hyperglycemic effect of vasotocin may be mediated via growth hormone.     

Hypoglycémie spontanée et insuffisance rénale chronique.

Although glucose intolerance occurs as a consequence of chronic renal failure, improvement of a diabetic state by deterioration of renal function is a well known phenomenon. Recently occasional cases of spontaneous hypoglycemia in patients with chronic renal failure have been reported; two such cases and the results of metabolic studies are described in this paper. Pituitary, thyroid and adrenal function appeared to be normal. The results of an oral glucose tolerance test were normal; an appropriate insulin response was demonstrated in one patient, and a slightly elevated basal insulin value with a delayed insulin response to oral administration of glucose was demonstrated in the other. An insulin tolerance test did not support the hypothesis of increased insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concentration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase insulin sensitivity as a factor, and the growth hormone response to hypoglycemia was normal. An intravenous glucagon test caused a subnormal increase in plasma glucose concnetration, and the intravenous administration of tolbutamide produced hypoglycemia without an increase in insulin values. The plasma alanine concentration was low and the proinsulin/insulin ratio was increased. The origin of this hypoglycemia is not clear but is probably multifactorial. However, low hepatic glycogen stores and inadequate gluconeogenesis due to substrate deficiency seem to be involved.     

Transient glucose intolerance during attacks of thyrotoxic periodic paralysis

In a 19-year-old Japanese male (case 1) with thyrotoxic periodic paralysis (TPP), an increase of plasma glucose concentration together with abnormally high levels of serum immunoreactive insulin (IRI) was observed preceding a spontaneous attack of paralysis. Therefore, the plasma glucose, glucagon, epinephrine, norepinephrine, serum IRI, growth hormone and cortisol levels, and the erythrocyte insulin receptors were measured in case 1 and a 40-year-old Japanese male (case 2) with TPP during attacks of paralysis induced by prolonged glucose loading. In case 1, the serum IRI concentration was elevated to the extraordinarily high level of 655.0 microU/ml at the beginning of paralysis, and at that time, the plasma glucose concentration was 147 mg/dl. However, when paralysis was not induced by a similar glucose loading during methimazole treatment, the serum IRI and plasma glucose levels at the corresponding time after glucose loading were 20.9 microU/ml and 87 mg/dl, respectively. Furthermore, the affinity of the erythrocyte insulin receptors was decreased during the attack. In case 2, plasma glucose and serum IRI concentrations were increased in accordance with the initiation of paralysis although the blood levels of hormones counteracting insulin were not significantly changed. These findings suggest that there is something interacting with the normal action of the insulin in the early phase of paralysis.     

Disruption of growth hormone receptor gene causes diminished pancreatic islet size and increased insulin sensitivity in mice

Growth hormone, acting through its receptor (GHR), plays an important role in carbohydrate metabolism and in promoting postnatal growth. GHR gene-deficient (GHR(-/-)) mice exhibit severe growth retardation and proportionate dwarfism. To assess the physiological relevance of growth hormone actions, GHR(-/-) mice were used to investigate their phenotype in glucose metabolism and pancreatic islet function. Adult GHR(-/-) mice exhibited significant reductions in the levels of blood glucose and insulin, as well as insulin mRNA accumulation. Immunohistochemical analysis of pancreatic sections revealed normal distribution of the islets despite a significantly smaller size. The average size of the islets found in GHR(-/-) mice was only one-third of that in wild-type littermates. Total beta-cell mass was reduced 4.5-fold in GHR(-/-) mice, significantly more than their body size reduction. This reduction in pancreatic islet mass appears to be related to decreases in proliferation and cell growth. GHR(-/-) mice were different from the human Laron syndrome in serum insulin level, insulin responsiveness, and obesity. We conclude that growth hormone signaling is essential for maintaining pancreatic islet size, stimulating islet hormone production, and maintaining normal insulin sensitivity and glucose homeostasis.     

Profound hypoglycemia in starved, ghrelin-deficient mice is caused by decreased gluconeogenesis and reversed by lactate or fatty acids

When mice are subjected to 7-day calorie restriction (40% of normal food intake), body fat disappears, but blood glucose is maintained as long as the animals produce ghrelin, an octanoylated peptide that stimulates growth hormone secretion. Mice can be rendered ghrelin-deficient by knock-out of the gene encoding either ghrelin O-acyltransferase, which attaches the required octanoate, or ghrelin itself. Calorie-restricted, fat-depleted ghrelin O-acyltransferase or ghrelin knock-out mice fail to show the normal increase in growth hormone and become profoundly hypoglycemic when fasted for 18-23 h. Glucose production in Goat(-/-) mice was reduced by 60% when compared with similarly treated WT mice. Plasma lactate and pyruvate were also low. Injection of lactate, pyruvate, alanine, or a fatty acid restored blood glucose in Goat(-/-) mice. Thus, when body fat is reduced by calorie restriction, ghrelin stimulates growth hormone secretion, which allows maintenance of glucose production, even when food intake is eliminated. In humans with anorexia nervosa or kwashiorkor, ghrelin and growth hormone are known to be elevated, just as they are in fat-depleted mice. We suggest that these two hormones prolong survival in starved humans as they do in mice.     

Effects of Soy-derived diets on plasma and liver lipids, glucose tolerance, and longevity in normal, long-lived and short-lived mice.

We examined the effects of diets based on a low isoflavone or a high isoflavone soy protein isolates in normal, growth-hormone receptor knockout and Ames dwarf, and Prop 1 (df) mice that are hypoinsulinemic, insulin-sensitive, and exceptionally long-lived, as well as in growth hormone transgenic mice that are hyperinsulinemic, insulin-resistant, dyslipidemic, and short-lived. Soybean diets tended to normalize plasma cholesterol levels in dwarf and transgenic mice, while low isoflavone diet reduced plasma triglycerides in most of the examined genotypes. The effects of low isoflavone and high isoflavone diets on the levels of free and esterified cholesterol in the liver were strongly genotype-dependent. Fasting blood glucose levels were reduced and glucose tolerance improved by both low isoflavone and high isoflavone diets in growth hormone-transgenic mice and in their normal siblings. Glucose tolerance was also improved by high-isoflavone diet in growth hormone receptor knockout mice. Lifespan was increased by low isoflavone diet in normal mice from two of the examined stocks. High isoflavone diet increased lifespan in normal animals from one line, but reduced lifespan of normal mice from a different line. We conclude that dietary soy protein intake can improve plasma and hepatic lipid profiles, reduce fasting glucose, enhance capacity for glucose tolerance, and prolong life, but all of these effects are strongly genotype-dependent.     

Acromegaly with 'normal' serum growth hormone levels. Clinical features, diagnosis and results of transsphenoidal microsurgery.

Among 216 consecutive patients with growth hormone secreting pituitary adenomas who underwent primary neurosurgical treatment at the University of Erlangen-Nürnberg, 8 cases of acromegaly with 'normal' basal growth hormone levels (less than or equal to 5 ng/ml) were seen. They all had the typical clinical features of acromegaly, exhibited an abnormal growth hormone secretion following an oral glucose load, and had markedly elevated somatomedin C levels. The GRH- and TRH/GnRH-tests were not found helpful in establishing the diagnosis. Neuroradiology could demonstrate a pituitary adenoma in all of the patients. Following transsphenoidal microsurgical resection of the tumours, growth hormone secretion during oral glucose tolerance testing was normalised in 7 of the 8 patients. Immunohistology and explant culture studies documented growth hormone secreting pituitary adenomas in all cases. The authors conclude that even the finding of repetitive 'normal' (less than or equal to 5 ng/ml) serum GH levels does not exclude active acromegaly and when the clinical diagnosis of acromegaly is suspected, dynamic endocrine testing may reveal abnormal secretion patterns of GH in these cases. Transsphenoidal microsurgical resection of a pituitary adenoma offers a good chance of clinical and endocrinological remission in these cases.     

Physiological relationships between growth hormone level, glycemia and metabolic control in dogs

This study was undertaken to explore the physiological relationships between fasting glycemia, antecedent glycemic control and fasting growth hormone levels in pancreatectomized dogs. In contrast to other studies, we used continuous intravenous infusions of insulin in an attempt not only to normalize fasting plasma glycemia but also to eliminate the characteristic fluctuations of diabetes usually encountered in the postprandial and postabsorptive periods. For comparison, a similar group of healthy animals served as normal controls. In the healthy dogs, fasting growth hormone (GH) levels were stable and well within normal limits for this species, demonstrating an overall mean +/- SD of 2.50 +/- 0.46 ng/ml. In the pancreatectomized group as a whole, the fasting GH levels were significantly elevated (4.63 +/- 2.42 ng/ml, P less than 0.01) and significantly (P less than 0.001) more variable than in the controls. Multiple regression and analysis of variance confirmed the expected significant positive correlation between fasting GH and fasting plasma glucose levels, but also elucidated a heretofore unknown direct relationship between fasting GH levels and the preceding instability of glycemic control.     

Increased adrenal androgen levels in patients with Prader-Willi syndrome are associated with insulin,IGF-I,and leptin,but not with measures of obesity

BACKGROUND/AIM: Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I. METHODS: In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone. RESULTS: The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them. CONCLUSIONS: In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect.     

Glucose regulates ghrelin, neuropeptide Y, and the GH/IGF-I axis in the tilapia, Oreochromis mossambicus

In general, a fish's ability to clear glucose is sluggish in relation to mammals, which has lead to the idea that fish are glucose intolerant. It has been reported that circulating glucose levels do fluctuate in response to environmental challenges. Recent reports suggest that glucose may function as a metabolic signal regulating ‘glucosensors’ in the brain in fish, as has been reported in mammals. The current study was designed to investigate the effect of glucose on ghrelin and neuropeptide Y (NPY) signaling in the brain, and on the growth hormone/insulin-like growth factor-I (GH/IGF-I) in the tilapia, Oreochromis mossambicus. Glucose treatment significantly increased plasma and stomach mRNA levels of ghrelin. In the brain, mRNA levels of the ghrelin receptor (GRLN-R) were significantly reduced, whereas NPY mRNA levels were significantly elevated; suggesting that NPY containing neurons may be a “glucosensor” as reported in mammals. Glucose treatment resulted in changes in the GH/IGF-I axis. Liver mRNA levels of both GH receptors (GHR1 and GHR2) were significantly elevated, whereas liver IGF-I mRNA were unaltered by glucose treatment. No change in plasma or pituitary mRNA levels of GH was observed. Glucose significantly reduced plasma IGF-I levels. These data show that glucose regulates endocrine factors involved in appetite, growth, and possibly energy homeostasis, and suggests that glucose may be acting as a signal of metabolic status in fish.     

Carbohydrate intolerance in gonadal dysgenesis: evidence for insulin resistance and hyperglucagonemia

To determine the pathogenesis of carbohydrate intolerance associated with gonadal dysgenesis, plasma glucose, insulin, glucagon, and growth hormone responses to oral glucose and intravenous tolbutamide, arginine and insulin were evaluated in 21 nonobese patients, 7-19 years old. Glucose intolerance was present in 9 of 21 nonobese patients (42.8%). Insulin levels, the area under the insulin curve after oral glucose and intravenous tolbutamide and the insulin to glucose ratio were significantly greater in patients than in controls (p less than 0.005). The decrease in plasma glucose following intravenous tolbutamide was significantly less in patients than in controls (p less than 0.05) despite insulin levels which were greater than in controls (p less than 0.05). After intravenous insulin, plasma glucose fell significantly less in patients than in controls (p less than 0.01). Plasma glucagon levels and the area under the glucagon curve after oral glucose and arginine infusion were significantly greater in patients than in controls (p less than 0.005 and p less than 0.01, respectively). The increase in glucagon after insulin-induced hypoglycemia was significantly less in patients than in controls (p less than 0.025). Fasting and stimulated growth hormone levels and the mean 24-hour growth hormone concentration were similar in patients and controls. These results indicate that glucose intolerance occurs frequently in gonadal dysgenesis and is associated with normal or increased insulin secretory responses. These abnormalities are probably due to insulin resistance and hyperglucagonemia. The decrease in insulin action does not appear to result from excessive growth hormone secretion or treatment with anabolic steroids or estrogen-progesterone medications.     

Aminergic regulation of neuroendocrinological functions: theoretical background and some clinical examples

Remarkable progress has been made during recent years in the central regulation of the hypothalamic releasing and inhibiting factors and the respective anterior pituitary hormones. There are two nearly universal inhibitory organizations: short tuberoinfundibular dopamine (TIDA) neurons and somatostatinergic system originating from the periventricular hypothalamus and terminating to the median eminence. It is now known that e.g. dopamine, noradrenaline and acetylcholine enhance while 5-hydroxytryptamine and GABA inhibit somatostatin secretion. These transmitters are also involved in the regulation of all releasing factors and pituitary hormones. Clinical applications have been developed based on the regulation of prolactin and growth hormone. Inhibitory TIDA neurons are undoubtedly the major determinants of prolactin secretion. Hyperprolactinaemia is one of the most common endocrinological side-effects of the drugs antagonizing dopaminergic transmission. Expectedly, dopaminergic drugs (bromocryptine, lergotrile, piribedil, dopamine and levodopa) are quite effective in reducing high prolactin levels regardless of the reason. The secretion of growth hormone is predominantly under dual dopaminergic control: hypothalamic stimulation and pituitary inhibition. The former masters the function of the normal gland, while the peripheral inhibitory component takes over in acromegalic gland. Hence dopaminergic drugs are able to reduce elevated growth hormone levels in 30-50% of the acromegalic patients. In normal man, dopamine agonists increase growth hormone levels. An analogous situation can be seen in Cushing's disease regarding ACTH secretion.     

Altered release of growth hormone from dispersed adenohypophysial cells of streptozotocin diabetic rats. I. Effects of growth hormone releasing factor and somatostatin

As growth hormone has been implicated in the "dawn phenomenon," an early morning rise in serum glucose, we have studied the control of growth hormone release in diabetes using an acutely dispersed system of adenohypophysial cells from normal or diabetic rats (65 mg/kg streptozotocin, 8 days before sacrifice; serum glucose, 490 +/- 17 mg/dL). Growth hormone release is normally controlled by the two hypothalamic hormones, growth hormone releasing factor and somatostatin. We have found cells of the diabetic rats exhibit changes in sensitivity that result in increased growth hormone release in static incubation. In normal cells, rat growth hormone releasing factor increases growth hormone release three- to four-fold with an EC50 of 151 +/- 27 pM (n = 7). In contrast, in cells from diabetic rats, there was a significant (twofold) increase in sensitivity to growth hormone releasing factor (EC50 = 75 +/- 15 pM, n = 7) which resulted in increased growth hormone release with lower but not maximal (10 nM) growth hormone releasing factor. Basal nonstimulated release was unchanged. Somatostatin inhibition of stimulated growth hormone release was reduced (n = 7); half-maximal inhibition occurred with 0.21 +/- 0.03 nM (normal) and 0.76 +/- 0.17 nM somatostatin (diabetic). In perifusion the peak secretion rate was significantly lower for diabetic cells stimulated by a maximal dose of growth hormone releasing factor. These studies suggest somatotrophs of diabetic rats have altered sensitivity in vitro to the controlling hormones growth hormone releasing factor and somatostatin.