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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopaminergic system seems to influence the regulation of insulin secretion, although in man conflicting data are reported. Furthermore, bromocriptine (BRC), a dopaminergic agonist, has been recently found to inhibit the seasonally occurring hyperinsulinemia and the increase in body weight in the hamster. On this basis, we investigated the effect of BRC on spontaneous and stimulated insulin secretion in human obesity. Six obese (BMI: 33.2 +/- 1.6 Kg/m2) underwent the administration of: 1) arginine (ARG, 0.5 g/Kg iv in 30 min), 2) BRC (2.5 mg po), 3) ARG+BRC. In each test plasma glucose and serum insulin, growth hormone (GH) and prolactin levels were determined. BRC did not significantly reduce spontaneous and ARG-induced insulin release. Baseline and stimulated glucose levels were also unchanged. BRC determined an increase in GH levels (3.7 +/- 1.3 vs 0.5 +/- 0.3 microgram/l, p < 0.05), but failed to modify the somatotrope responsiveness to ARG. On the other hand, both spontaneous and stimulated PRL secretion were reduced by BRC (2.5 +/- 0.4 vs 6.7 +/- 1.1 micrograms/l, p < 0.05 and 0.8 +/- 1.9 vs 11.0 +/- 2.1 micrograms/l, p < 0.05, respectively). Our results show that in obese patients the acute activation of dopaminergic receptors by bromocriptine fails to modify both basal and ARG-induced insulin release, while inhibits spontaneous and stimulated PRL secretion. Our data also show that the low GH response to arginine in obesity is not improved by the coadministration of bromocriptine, in agreement with the hypothesis that both substances act by the same mechanism, i.e. inhibition of endogenous somatostatin release.
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PMID:Effect of bromocriptine on insulin, growth hormone and prolactin responses to arginine in obesity. 886 1

The possibility that the growth hormone (GH) suppression associated with obesity is due to alterations in hypothalamic GH-releasing hormone (GHRH) and/or somatostatin (SRIH) has been considered, but the data are not consistent. In the present study, we sought to clarify the roles of GHRH and SRIH in obesity by using in situ hybridization to localize and quantify the level of expression of GHRH mRNA- and SRIH mRNA-containing neurons in the hypothalamus of male and female lean and obese Zucker rats (12 weeks of age; n = 6 per group). In lean animals, the number of GHRH mRNA-expressing cells in the arcuate nucleus and SRIH mRNA-containing neurons in the periventricular nucleus was 2- to 3-fold higher in males compared to females. The obese phenotype in the male was associated with a striking reduction in arcuate GHRH mRNA expression, both in terms of number of cells (-71%; p < 0.01) and grains/cell (-44%; p < 0.05). In contrast, in obese females, there was a marked augmentation (+ 175%; p < 0.05) in the number of GHRH mRNA-containing cells in the arcuate nucleus compared to their lean littermates. The small population of GHRH mRNA-containing neurons of the ventromedial nucleus was not modified in male obese rats, while it was considerably increased (p < 0.05) in obese females. Neither the number of labeling density of SRIH mRNA-containing neurons in the periventricular and arcuate nuclei of obese rats of either sex was changed when compared to their sex-matched lean counterparts. These results demonstrate that: (1) the obese male Zucker rat exhibits a marked diminution in hypothalamic GHRH mRNA expression, while a reverse pattern is evident in the obese female; (2) hypothalamic SRIH mRNA-containing neurons are not significantly altered in obese rats of both sexes. Our findings suggest that the impaired GH secretion of the obese Zucker rat is due, at least in part, to alterations in hypothalamic GHRH gene expression and that SRIH does not play a major role.
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PMID:Sex-related alterations in hypothalamic growth hormone-releasing hormone mRNA-but not somatostatin mRNA-expressing cells in genetically obese Zucker rats. 887 36

The synthetic growth hormone-releasing peptides (GHRPs) and their nonpeptide analogues release growth hormone (GH). They are not only effective parenterally, but also intranasally and if given in the appropriate doses, they are active orally as well. The exact mechanism of action has not been fully established. There is probably a dual site of action. According to experiments on in vitro pituitary membranes, they directly stimulate GH secreting cells, but they are also active in the hypothalamus. This latter site of effect seems to be the more important in vivo. The presence of the endogenous growth hormone-releasing hormone (GHRH) is needed for their full action in humans. Their hypothalamic action involves either direct stimulation of GHRH neurons, or/and they act as functional somatostatin antagonists or possibly they act via an unknown hypothalamic factor. Intravenous administration causes marked GH release in humans and GHRPs synergise with GHRH in causing high GH output. They release GH in short stature children and in growth hormone deficient adults and in other situations of GH deficiency, such as obesity, catabolic diseases and old age. The role of GHRPs in the diagnosis and treatment of GH deficient states requires further wide-spread investigations.
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PMID:[Growth hormone-releasing peptides (GHRP) and their analogues]. 899 95

The growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis is subject to exquisite regulation by multiple internal physiological variables and external cues. This review and update summarizes the impact of age, obesity, gonadal function and sleep on the control of GH secretion by the pituitary gland, as regulated by the dominant hypothalamic regulatory peptides, GH-releasing hormone (GHRH) and somatostatin. Available studies show an exponential decline in the calculated daily GH-secretion rate as a function of age in healthy men, such that every 7 years of advancing age beyond age 18-21 results in an approximately 50% decline. There are also strongly negative correlations between the daily GH-secretion rate and indices of obesity, such as the body mass index (BMI). For each increase in BMI of 1.5 kg/m2, there is a 50% decrease in the amount of GH secreted per day. At puberty, and across a span of adult ages, gonadal steroid-hormone concentrations in blood positively determine GH release. In particular, serum estradiol and testosterone concentrations are proportionate to GH-secretory burst mass and mean serum GH concentrations. Deep sleep (stages 3 and 4) is accompanied by markedly increased pulsatile GH secretion that can be accounted for mechanistically by presumptive somatostatin withdrawal combined with hypothalamic GHRH release. Lastly, body composition (especially visceral adiposity) appears to be a dominant negative determinant of GH production, since the relationships between GH secretion and age, testosterone, or sleep are all attenuated or abolished by adiposity. Recent data using pulsatile GHRH treatment or pharmacological methods to reduce somatostatin secretion point to combined defects in GHRH release and somatostatin excess as the most plausible pathophysiology of hyposomatotropism accompanying obesity.
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PMID:Physiological regulation of the human growth hormone (GH)-insulin-like growth factor type I (IGF-I) axis: predominant impact of age, obesity, gonadal function, and sleep. 908 16

Growth hormone-releasing peptides (GHRPs) are synthetic, non-natural peptides endowed with potent stimulatory effects on somatotrope secretion in animals and humans. They have no structural homology with GHRH and act via specific receptors present either at the pituitary or the hypothalamic level both in animals and in humans. The GHRP receptor has recently been cloned and, interestingly, it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. The mechanisms underlying the GHRP effect are still unclear. At present, several data favor the hypothesis that GHRPs could act by counteracting somatostatinergic activity both at the pituitary and the hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. GHRP-6 was the first hexapeptide to be extensively studied in humans. More recently, a heptapeptide, GHRP-1, and two other hexapeptides, GHRP-2 and Hexarelin, have been synthesized and are now available for human studies. Moreover, non-peptidyl GHRP mimetics have been developed which act via GHRP receptors and their effects have been clearly demonstrated in animals and in humans in vivo. Among non-peptidyl GHRPs, MK-0677 seems the most interesting molecule. The GH-releasing activity of GHRPs is marked and dose-related after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHRPs is reproducible and undergoes partial desensitization, more during continuous infusion, less during intermittent administration: in fact, prolonged administration of GHRPs increases IGF-1 levels both in animals and in humans. The GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations. It increases from birth to puberty, persists at a similar level in adulthood and decreases thereafter. By the sixth decade of life, the activity of GHRPs is reduced but it is still marked and higher than that of GHRH. The GH-releasing activity of GHRPs is synergistic with that of GHRH, is not affected by opioid receptor antagonists, such as naloxone, and is only blunted by inhibitory influences, including neurotransmitters, glucose, free fatty acids, gluco corticoids, recombinant human GH and even exogenous somatostatin, which are known to almost abolish the effect of GHRH. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as in acromegaly, anorexia nervosa and hyperthyroidism. On the other hand, their good GH-releasing activity has been shown in some but not in other somatotrope hyposecretory states. In fact, reduced GH responses after GHRP administration have been reported in idiopathic GH deficiency as well as in idiopathic short stature, in obesity and in hypothyroidism, while in patients with pituitary stalk disconnection or Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. In short children an increase in height velocity has also been reported during chronic GHRP treatment. Thus, based on their marked GH-releasing effect even after oral administration, GHRPs offer their own clinical usefulness for treatment of some GH hyposecretory states.
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PMID:Growth hormone-releasing peptides. 918 61

Glucose load has a biphasic effect on GH secretion. In fact, in normal subjects, glucose load has a prompt inhibitory and a late stimulatory effect on both spontaneous and GHRH-induced GH levels. The mechanism underlying the inhibitory effect is probably mediated by the increase in hypothalamic somatostatin, whereas that underlying the stimulatory effect is unclear. On the other hand, in obesity, a reduced somatotrope responsiveness to all GH secretagogues is well known, whereas recently, we found that glucose load, but not pirenzepine and somatostatin, fails to inhibit the GHRH-induced GH rise. Thus, the inhibitory effect of hyperglycemia on GH secretion is selectively lacking in obesity. The aim of the present study was to verify whether in obesity the late stimulatory effect of glucose on GH secretion is preserved. We studied 15 female obese patients (OB; age, 33.9 +/- 2.6 yr; body mass index, 36.4 +/- 1.5 kg/m2; waist/hip ratio, 0.9 +/- 0.1) and 12 normal female subjects (NS; 26.5 +/- 1.0 yr; 21.4 +/- 0.3 kg/m2) as controls. Two studies were performed. In study A (six OB and six NS) we evaluated the somatotrope response to GHRH (1 microgram/kg, i.v., at 0 min) alone or preceded by oral glucose (OGTT; 100 g, orally, at -45 min). In study B (nine OB and six NS) we studied the somatotrope response to OGTT (100 g, orally, at 0 min), saline plus GHRH (1 microgram/kg, iv, at 150 min), and OGTT plus GHRH. In study A, the GHRH-induced GH rise in NS was higher (P < 0.01) than that in OB. OGTT blunted the GHRH-induced GH rise in NS (0-90 min area under the curve, 318.9 +/- 39.1 vs. 696.3 +/- 110.8 micrograms/min-L; P < 0.05), but failed to modify it in OB (289.1 +/- 51.7 vs. 283.9 +/- 44.0 micrograms/min-L). In study B, the GHRH-induced GH rise in NS was higher (P < 0.01) than that in OB. OGTT induced a late GH increase in both NS (150-240 min area under the curve, 249.6 +/- 45.2 micrograms/min-L) and OB (103.2 +/- 31.4 micrograms/min-L). Moreover, OGTT enhanced the GHRH-induced GH rise in NS as well as in OB [1433.0 +/- 202.0 vs. 967.9 +/- 116.3 micrograms/min-L (P < 0.03) and 763.8 +/- 131.0 vs. 278.1 +/- 52.3 micrograms/min-L (P < 0.01), respectively]. The GH responses to OGTT alone and combined with GHRH in OB were lower (P < 0.03) than those in NS. Our data show that in human obesity, the oral glucose load loses its precocious inhibitory effect on the GHRH-induced GH rise but maintains its late stimulatory effect on somatotrope secretion. These findings suggest that the inhibitory and stimulatory effects of glucose load on GH secretion are unlikely to be due to biphasic modulation of hypothalamic somatostatin release, which seems selectively refractory to stimulation by hyperglycemia in obesity.
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PMID:In obesity, glucose load loses its early inhibitory, but maintains its late stimulatory, effect on somatotrope secretion. 921 4

In human obesity, spontaneous and GRF stimulated growth hormone secretion have been shown to be blunted. We used cafeteria diet fed obese rats as a model to study the central mechanisms involved in growth hormone secretion changes which are observed in obesity. We analysed somatostatin messenger RNA and protein levels in the hypothalamic periventricular nucleus of the rats by non radioactive in situ hybridization and immunocytochemistry respectively. The optical density of somatostatin mRNA, measured by a computerized image system, was significantly higher in cafeteria diet fed rats (1014 +/- 87 vs 444 +/- 45; p < 0.05). The integrated optical density of somatostatin protein was also significantly higher in cafeteria rats compared to the control rats (222 +/- 36 vs 114 +/- 24; p < 0.05). In conclusion, cafeteria diet induced obese rats have a higher somatostatin biosynthesis in the periventricular nucleus. Further studies are needed to establish the possible link of this increased somatostatin gene expression with the decreased GH production.
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PMID:Cafeteria diet-induced obese rats have an increased somatostatin protein content and gene expression in the periventricular nucleus. 925 5

Growth hormone-releasing peptides (GHRPs) are a series of hepta (GHRP-1)- and hexapeptides (GHRP-2, GHRP-6, Hexarelin) that have been shown to be effective releasers of GH in animals and humans. More recently, a series of nonpeptidyl GH secretagogues (L-692,429, L-692,585, MK-0677) were discovered using GHRP-6 as a template. Some cyclic peptides as well as penta-, tetra-, and pseudotripeptides have also been described. This review summarizes recent developments in our understanding of the GHRPs, as well as the current nonpeptide pharmacologic analogs. GHRPs and their analogs have no structural homology with GHRH and act via specific receptors present at either the pituitary or the hypothalamic level. The GHRP receptor has recently been cloned and it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. Although the exact mechanism of action of GHRPs has not been fully established, there is probably a dual site of action on both the pituitary and the hypothalamus, possibly involving regulatory factors in addition to GHRH and somatostatin. Moreover, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. The marked GH-releasing activity of GHRPs is reproducible and dose-related after intravenous, subcutaneous, intranasal, and even oral administration. The GH-releasing effect of GHRPs is the same in both sexes, but undergoes age-related variations. It increases from birth to puberty and decreases in aging. The GH-releasing activity of GHRPs is synergistic with that of GHRH and not affected by opioid receptor antagonists, while it is only blunted by inhibitory influences that are known to nearly abolish the effect of GHRH, such as neurotransmitters, glucose, free fatty acids, glucocorticoids, rhGH, and even exogenous somatostatin. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states, such as acromegaly, anorexia nervosa, and hyperthyroidism. On the other hand, GHRPs and their analogs have been reported to be effective in idiopathic short stature, in some situations of GH deficiency, in obesity, and in hypothyroidism, while in patients with pituitary stalk disconnection and in Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. A potential role in the treatment of short stature, aging, catabolic states, and dilated cardiomyopathy has been envisaged.
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PMID:Growth hormone-releasing peptides and their analogs. 946 89

Hirsutism, acne and androgenic alopecia represent, in females, some of the manifestations of the clinical spectrum of hyperandrogenism. These pictures represent not only cosmetic damage, but also a source of remarkable psychological distress. Often hirsutism is regarded as presumptive evidence of a lack of femininity. The major diagnostic concern is to exclude an ovarian or adrenal androgen-secreting tumor, a congenital hyperplasia or polycystic ovary disease. Ethnic background should be taken into account together with the progression of the symptoms. Following the etiology, surgery and exogenous glucocorticoids or inhibition of gonadotropin secretion have to be carefully chosen in the management of different kinds of hyperandrogenism. Several pharmacologic agents have recently shown the ability to block the androgen receptors at target organ sites, thus allowing a specific antiandrogenic treatment. In some cases cosmetic measures could be of great value. Obesity accompanied by hyperinsulinemia can represent the main cause of ovary androgen hypersecretion; therefore a reduced body weight and muscle activity represent the basis of any treatment. Some other drugs, such as long-acting analogs of somatostatin, could be considered among possible drugs for the future. The aim of this article is to provide an appraisal of what is presently known about the regulation of hair growth, the various causes of excessive androgen secretion and the current methods to solve, safely, this important feminine clinical problem.
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PMID:Treatment of androgen excess in females: yesterday, today and tomorrow. 947 91

The aim of this study was to test the hypothesis that plasma leptin concentrations contributed to the pathophysiology of NIDDM by decreasing both insulin-mediated glucose disposal and glucose-stimulated insulin secretion. The study was performed in 60 women with normal oral glucose tolerance. Differences in insulin-mediated glucose disposal were determined by comparing the steady-state plasma glucose (SSPG) concentrations attained at the end of a 180-min constant infusion of somatostatin, glucose, and insulin, while comparisons of glucose-stimulated insulin secretion were based on the incremental increase in insulin concentration 30 min after an oral glucose challenge (deltaIns) as compared with the fasting value. The results showed that the higher the fasting plasma leptin concentration, the greater the degree of insulin resistance (r = 0.47, P < 0.01). Furthermore, multiple regression analysis indicated that the relationship between leptin and SSPG was independent of age and degree of obesity as estimated by BMI. However, since the total integrated plasma insulin response was highly correlated with both SSPG (r = 0.80, P < 0.001) and leptin (r = 0.55, P < 0.01), multiple regression analysis was repeated, adding total insulin response to the model. When this was done, the significant relationship between leptin and SSPG disappeared, whereas both BMI (P < 0.03) and insulin response (P < 0.001) were correlated with SSPG. A significant relationship between leptin and deltaIns was seen, but it was a positive one (r = 0.31, P < 0.02), not a negative one as would be expected if circulating levels of leptin inhibited glucose-stimulated insulin secretion. Furthermore, multiple regression analysis could only confirm an independent relationship between deltaIns and SSPG, but not between deltaIns and leptin. The results of these studies do not support the view that circulating leptin has a primary effect on either insulin action or secretion in normal female volunteers. It seems more likely that chronic hyperinsulinemia in insulin-resistant individuals acts to increase adipose tissue leptin synthesis and secretion, leading to higher ambient leptin concentrations.
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PMID:Plasma leptin concentrations do not appear to decrease insulin-mediated glucose disposal or glucose-stimulated insulin secretion in women with normal glucose tolerance. 951 20


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