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Biomedical subjects

E Ghigo

Publications and source records attributed to E Ghigo.

At least 91 records · Page 5Linked to original sources
PubMed2002

Natural (ghrelin) and synthetic (hexarelin) GH secretagogues stimulate H9c2 cardiomyocyte cell proliferation.

Recent experimental data demonstrate cardiovascular effects of the GH secretagogues (GHSs) hexarelin and ghrelin, the proposed natural ligand for the GHS receptor. Moreover, specific cardiac binding sites for GHSs have been suggested. The aim of the present study was to investigate if the natural ligand ghrelin and synthetic GHS peptide hexarelin and analogues have direct effects on the cardiomyocyte cell line, H9c2. Hexarelin stimulated thymidine incorporation in a dose-dependent manner with significant responses at 3 micro M (147+/-3% of control, P<0.01) and elicited maximal effects at concentrations around 30 micro M. This activity was seen already after 12 h of incubation with a maximal effect after 18 h (176+/-9% of control, P<0.01). Ghrelin also had a significant stimulatory effect on thymidine incorporation (129+/-2% of control at 3 micro M and 18 h, P<0.05). The stimulatory effect on thymidine incorporation of hexarelin, Tyr-Ala-hexarelin, EP80317 and ghrelin was specific and no stimulatory effect was observed with the truncated GH-releasing peptide EP51389 or the non-peptidyl GHS MK-0677. In competitive binding studies, (125)I-labeled Tyr-Ala-hexarelin was used as radioligand and competition curves showed displacement with hexarelin, Tyr-Ala-hexarelin, EP80317 and ghrelin, whereas MK-0677 and EP51389 produced very little displacement at 1 micro M concentration, adding further support for an alternative subtype binding site in the heart compared with the pituitary. In conclusion, we have demonstrated a dose-dependent and specific stimulation of cardiomyocyte thymidine incorporation by natural and synthetic GHS analogues, suggesting increased cell proliferation and binding of GHS to H9c2 cardiomyocyte cell membranes. These findings support potential peripheral effects of GHS on the cardiovascular system independent of an increased GH secretion.

Binding, Competitive↗
PubMed2002

Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-I axis to obesity.

Obese patients show marked impairment in spontaneous secretion as well as in the somatotroph responsiveness to all provocative stimuli. GH insufficiency in obese patients has been reported reversible after long-term diet and marked weight loss but somatotroph secretion is not restored by fasting. Among potential neuroendocrine causes, GHRH hypoactivity has been shown but it is likely that alterations in the influence of ghrelin, the gastric-derived natural ligand of the GHS-R, and or of the NPY/leptin interplay could have a role. Among metabolic alterations, the chronic elevation of FFA levels and hyperinsulinism probably have a key role in causing GH insufficiency in obesity. Despite marked GH insufficiency, total IGF-I levels are basically preserved while free IGF-I levels are even increased thus questioning real hypoactivity of GH/IGF-I axis in obesity. Peripheral GH hypersensitivity due to increased GH receptor status, hyperinsulinism and reduced IGFBP-I levels likely explain almost normal total IGF-I and increased free IGF-I levels which, in turn, probably exert an increased negative feedback action on somatotroph cells.

Adaptation, Physiological↗
PubMed2001

Thyroid function and anti-thyroid antibodies in MS patients screened for interferon treatment. A multicenter study.

Interferon beta (IFNB) treatment for multiple sclerosis (MS) has been associated with thyroid disorders (TD), in particular in patients with subclinical TD or anti-thyroid (AT) autoantibodies (autoAb) before starting treatment. TD and AT autoAb frequency was reported increased in MS. To determine whether MS patients have subclinical thyroid function abnormalities or anti-thyroid autoimmunity predisposing to develop TD, we performed a prospective multicenter screening of thyroid function and autoimmunity in 152 relapsing-remitting (RR) MS patients selected to receive IFNB treatment and in 437 healthy normothyroidal controls. Thyroid-related hormones and anti-thyroid microsomal antigen (anti-TMA) autoAb were tested with sensitive immunoradiometric or chromatographic assays. Cases were stratified for different progressively decreasing or increasing cutoff values of thyroid-stimulating hormone (TSH) (0.3, 0.2, 0.1, 3 and 5 mIU/l), and odds ratios (OR) with 95% confidence intervals (CI) calculated using logistic regression adjusted for gender, age, and anti-TMA autoAb positivity. The frequency of cases below or above the TSH cutoff values was not significantly different in MS patients and controls, and the risk to have an abnormal TSH level was not significantly increased in MS patients (OR ranging 0.37-0.84; CI, 0.05-3.01), even if anti-TMA autoAb positive (OR ranging 0.35-0.85; CI, 0.04-3.00). Frequencies of subclinical hypothyroidism and of anti-TMA autoAb positivity were, however, trending higher in MS men (ranging 5-7%) than in controls (3%). MS patients do not have an increased risk of subtle thyroid function abnormalities, subclinical TD, or anti-TMA autoAb positivity that may predispose to develop thyroid dysfunction during IFNB treatment. The positive trend for subclinical hypothyroidism and anti-TMA autoAb positivity, however, advises a longitudinal study of thyroid function and autoimmunity during IFNB treatment to see whether patients with baseline subclinical thyroid dysfunction develop clinically significant alteration during treatment.

Adolescent↗
PubMed2001

Cortistatin, but not somatostatin, binds to growth hormone secretagogue (GHS) receptors of human pituitary gland.

Antagonism between GH secretagogues (GHS) and somatostatin (SRIH) has been postulated and demonstrated, but SRIH does not bind to GHS receptors (GHS-R) and potent synthetic peptidyl GHS (GHRP6, hexarelin) do not displace radiolabeled SRIH from its receptors. However, non-natural SRIH octapeptide agonists (mainly lanreotide and vapreotide) displace 125I-Tyr-Ala-hexarelin from pituitary binding sites suggesting that an endogenous factor related to SRIH might exist and interact with GHS-R. Our aims were to investigate the ability of different SRIH-like peptides such as various SRIH fragments (SRIH 3-14, SRIH 7-14, SRIH 3-10, SRIH 7-10, SRIH 2-9) and a natural neuropeptide that shows a high structural homology with SRIH such as cortistatin-14 (CST) to compete with 125I-Tyr-Ala-hexarelin for human pituitary binding sites and to compare their binding affinity with that of hexarelin and ghrelin, a gastric-derived peptidyl GHS that has been proposed as a natural ligand of GHS-R. While the binding of 125I-Tyr-Ala-hexarelin to pituitary membranes was completely displaced by unlabelled hexarelin, ghrelin and CST, none of the SRIH fragments tested inhibited this binding. Ghrelin and CST exhibited a similar affinity (4.6-5.4 x 10(-7) mol/l) for the binding while hexarelin was more effective by about four orders of magnitude in displacing 125I-Tyr-Ala-hexarelin. Our data demonstrate for the first time that cortistatin, a natural peptide related to SRIH, binds to GHS-R and suggest that this factor may play a role in modulating the activity of these receptors.

Adult↗
PubMed2001

Recombinant human IGF-I does not modify the ACTH and cortisol responses to hCRH and hexarelin, a peptidyl GH secretagogue, in humans.

An inhibitory influence of insulin-like growth factor-I (IGF-I) on hypothalamus-pituitary-adrenal (HPA) axis has been hypothesized. In fact, it has been reported that the rhGH (recombinant human GH)-induced IGF-I increase inhibits both cortisol and GH response to MK-0677, a non-peptidyl GH secretagogue in animals. The aim of this study was to further clarify the inhibitory role, if any, of IGF-I on corticotroph function. We studied the effect of rhIGF-I (recombinant human IGF-I; 20 microg/kg s.c. at -180 min) or placebo on the ACTH and cortisol responses to hCRH (human CRH; 2.0 microg/kg i.v. at 0 min) or hexarelin (HEX; 2.0 microg/kg i.v. at 0 min), a peptidyl GHS, in normal young women. The effect of rhIGF-I on the GH response to HEX was also studied. The subjects were six normal young women [age: 26-35 yr; body mass index (BMI): 19-23 kg/m2] in their early follicular phase. The results showed that after s.c. rhIGF-I administration, circulating IGF-I levels increased approximately 77%, peaking at -60 min and persisting similar up to +120 min. The mean ACTH, cortisol and GH concentrations did not change from -180 to 0 min when evaluated after both placebo or rhIGF-I. CRH and HEX induced similar ACTH (peak vs baseline, mean+/-SE: 47.5+/-10.9 vs 21.3+/-3.0 pg/ml and 30.3+/-6.9 vs 19.2+/-3.8 pg/ml, respectively; p<0.04) and cortisol responses (177.5+/-5.4 vs 109.3+/-10.3 microg/l and 149.4+/-12.3 vs 119.8+/-16.4 microg/l, respectively, p<0.04). RhIGF-I pretreatment did not modify the ACTH and cortisol responses to hCRH (46.0+/-13.8 pg/ml and 181.1+/-16.9 microg/l, respectively) as well as those to HEX (28.8+/-5.0 pg/ml and 144.1+/-16.2 microg/l, respectively). On the other hand, the GH response to HEX was clearly reduced by rhIGF-I (23.9+/-4.7 vs 64.7+/-14.8 microg/l, p<0.05). Our findings show that rhIGF-I-induced increase of circulating IGF-I levels exerts negative feedback action on somatotroph secretion, while it does not modify the corticotroph and the adrenal responsiveness to CRH or hexarelin.

Adrenocorticotropic Hormone↗
PubMed2001

Binding of 125I-labeled ghrelin to membranes from human hypothalamus and pituitary gland.

Ghrelin has been proposed as a natural ligand of the GH secretagogue receptor(s) (GHS-R), which was an orphan receptor activated by synthetic peptidyl (hexarelin) and non-peptidyl (MK-0677) GHS to strongly release GH in animals and humans. Herein we studied: 1) the binding of 125I-labeled human ghrelin to membranes from human hypothalamus and pituitary gland; 2) the ability of human ghrelin (either octanoylated or desoctanoylated), as well as of some GHS and neuropeptides to compete with the radioligand. The saturation binding analysis showed, in both tissues, the existence of a single class of high-affinity binding sites with limited binding capacity. The Bmax (maximal number of binding sites) values of ghrelin receptors in the hypothalamus were significantly greater (p<0.001) than those detected in the pituitary, whereas the Kd (dissociation constant) values in the two tissues were similar. 125I-ghrelin bound to hypothalamic membranes was displaced by ghrelin, hexarelin, MK-0677, various GHS antagonists (EP-80317, [D-Arg1-D-Phe5-D-Trp7,9-Leu11]-substance P) and some natural (cortistatin-14) and synthetic (vapreotide) SRIH-14 agonists. In contrast, no competition was seen in the presence of GHRH-44, SRIH-14 or desoctanoylated ghrelin, a ghrelin precursor that is devoid of GH-releasing properties. In conclusion, this preliminary study firstly demonstrates that ghrelin needs octanoylation to bind its hypothalamo-pituitary receptors. These receptors are the specific binding sites for GHS and their antagonists, as well as for SRIH analogs (vapreotide and cortistatin- 14), but not for native SRIH.

Binding, Competitive↗
PubMed2001

Neuroendocrine effects of subcutaneous sumatriptan in patients with migraine.

We evaluated the sensitivity of 5-HT1D receptors in patients with migraine using sumatriptan as a pharmacological probe. The drug inhibits the release of ACTH, cortisol and prolactin and this effect may be used to explore the function of serotoninergic systems in vivo. We administered sumatriptan (6 mg sc) and placebo to 15 migraineurs, during the headache-free period, and to 10 healthy controls. Blood samples were collected -15, 0, 15, 30, 45, 60 and 90 min after injections. Sumatriptan induced a significant (p<0.01) decrease of ACTH, cortisol and prolactin concentrations both in patients with migraine and in controls. The neuroendocrine response was not significantly different in the two groups. Our results suggest that 5-HT1D receptor sensitivity is not altered in migraine.

Adrenocorticotropic Hormone↗
PubMed2001

Growth hormone-inhibiting activity of cortistatin in the rat.

Cortistatin-14 (CST-14) is an endogenous neuropeptide with notable structural similarities to native somatostatin-14 (SS-14), but different physiological functions. Differences in the physiology of the two peptides do not provide conclusive evidence for a specific receptor for CST. To date, the effects of CST-14 on anterior pituitary hormones have never been reported. Aim of this study was to investigate the in vivo effects of CST-14 on GH secretion in comparison to SS-14. Our results demonstrate that CST-14 was very effective in reducing GH secretion in normal male anaesthetized rats. Its activity was similar to that of SS-14 and had a rapid onset and a slightly longer duration of action. In conclusion, we have reported for the first time that CST is a potent and effective inhibitor of GH release in rats and that its action may be mediated by the interaction with one or different SS receptor subtypes.

Animals↗
PubMed2001

Short procedure of GHRH plus arginine test in clinical practice.

Either in children or in adults, arginine (ARG) alone and combined with GHRH (GHRH+ARG) are reliable tests for the diagnosis of GH deficiency. The procedures of these tests generally include GH measurement every 15 min from baseline up to 90-120 min. Aim of our study was to verify if the procedure of these tests could be usefully shortened in clinical practice. To this goal we have studied 173 normally growing children and adolescents (C, 117 M and 56 F, age: 11.3 +/- 0.4 yr.) and 125 young and middle aged normal adults (A, 68 M and 57 F, age: 30.0 +/- 0.6 yr.). ARG alone test was performed by 81 C and 33 A (0.5 g/kg arginine, i.v., from 0 to +30 min, up to a maximum of 30 g) while GHRH (1 microg/kg i.v. bolus at 0 min) + ARG test was performed by 92 C and 92 A. After ARG alone, taking into account data from +15 to +105 min, GH values above the 3rd centile limit of arbitrary cut-off (7 or 10 microg/l in C and 5 microg/l in A) occurred in 85% or 64% and 94% subjects, respectively. After GHRH+ARG test, taking into account only data at +30, +45, +60 min GH values above the 3rd centile limit (20 microg/l in C and 16.5 microg/l in A) occurred in 99% of subjects in both groups. Taking into account only these 3 timing points, the percentage of GH peak above the third centile limits after ARG alone was never higher than 60% in C and 85% in A. In conclusion, this study shows that single GHRH+arginine test can be reliably performed in a shortened procedure which makes easier the clinical practice and further reduces costs.

Adolescent↗
PubMed2001

Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with simple obesity. Comparison with normal subjects and hypopituitary patients with severe GH deficiency.

OBJECTIVE: Reduction of growth hormone (GH) secretion in obesity probably reflects neuroendocrine and metabolic abnormalities. Even short-term fasting stimulates GH secretion and distinguishes normal from hypopituitary subjects with growth hormone deficiency (GHD). Marked weight loss improves GH secretion in obesity but the effect of fasting is controversial. We studied the effects of a 36 h fasting on the GH/IGF-I axis and metabolic parameters in obesity. SUBJECTS: We studied nine obese patients (OB; three male and six female; age, 29.2+/-4.8; range, 18-59 y; body mass index (BMI), 43.4+/-2.7 kg/m(2); WHR, 0.9+/-0.1). Fifteen normal subjects (NS; eight male and seven female 28.9+/-0.6, 25-35 y; 21.6+/-0.4 kg/m(2)) and 10 adult hypopituitary patients with severe GH deficiency (GHD; seven male and three female; 37.6+/-2.3, 29-50 y; 24.5+/-1.0 kg/m(2); GH peak<3 microg/l after ITT and/or<9 microg/l after GHRH+arginine) served as control groups. STUDY DESIGN: We studied the effects of 36 h fasting on 8 h diurnal mean GH, insulin and glucose concentrations (mGHc, mINSc and mGLUc; assay every 30 min from 8.00 am to 4.00 pm) as well as on IGF-I, IGFBP-3, ALS, IGFBP-1, GHBP and free fatty acid (FFA) levels. RESULTS: Before fasting, basal IGF-I and ALS levels in OB were similar to those in NS and both were higher (P<0.001) than those in GHD. IGFBP-3 levels in OB were lower (P<0.01) than in NS but higher (P<0.02) than in GHD. GHBP levels in OB and GHD were similar and both were higher (P<0.01) than in NS. Glucose levels were similar in all groups. FFA levels in OB were higher (P<0.01) than in NS but similar to those in GHD. IGFBP-1 in OB were lower (P<0.05) than in NS and GHD which, in turn, were similar. On the other hand, mINSc in OB was higher (P<0.01) than that in NS and GHD which, in turn, were similar. The mGHc in OB was similar to that in NS but only the latter was higher (P<0.05) than in GHD. The individual mGHc in the three groups overlapped. After fasting, IGF-I levels in GHD were unchanged while they decreased in OB (P=NS) as well as in NS (P<0.01). IGFBP-3 and ALS levels did not change. GHBP levels in OB and GHD were unchanged while they increased in NS (P<0.01). Glucose and FFA levels were reduced and increased, respectively, in all groups (P<0.02 and P<0.01). IGFBP-1 increased while mINSc decreased in all groups (P<0.02 and P<0.01); in OB they persisted lower and higher (P<0.01) respectively, than in NS and GHD. Fasting significantly increased mGHc in NS (P<0.001) but not in OB as well as in GHD. Individual mGHc in OB showed persistent overlap with GHD. CONCLUSIONS: Short-term fasting does not increase GH secretion in obesity and does not distinguish somatotroph function in obese from that in severe GHD adults. Short-term fasting in obesity has attenuated effects on insulin and IGFBP-1 secretion while it normally increases free fatty acids in spite of any change in GH secretion.

Adolescent↗
PubMed2001

Effect of IGF-I administration on growth hormone secretion in obese subjects.

OBJECTIVE: The reduction of spontaneous and stimulated growth hormone (GH) secretion in obesity could reflect an increase of the inhibitory effect of insulin growth factor I (IGF-I) on somatotroph secretion. DESIGN: In the present study we aimed to verify the effect of low dose recombinant human IGF-I (20 microg/kg subcutaneously (s.c.) at 0 min) on 3 h-spontaneous GH secretion (mGHc, 0-180 min) and on the GH response to growth hormone releasing hormone (GHRH) (1 microg/kg i.v. at+180 min) in obesity. SUBJECTS: Five obese women with abdominal adiposity (OB, age, mean+/-s.e.m.: 31+/-7.13 y; BMI: 32.04+/-3.69 kg/m(2)) and eight age-matched lean women (NW, 28.3+/-1.2 y; 20.1+/-0.5 kg/m(2)) were studied. RESULTS: The mGHc and GHRH-induced GH response in OB (1.0+/-0.7 microg/l; AUC(180-270 min): 688.6+/-202.4 microg/l min, respectively) were lower than in NW (2.6+/-0.8 microg/l, 1315.9+/-189.9 microg/l min, respectively, P<0.05). The administration of rhIGF-I increased circulating IGF-I levels in OB and NW to the same extent (339.0+/-50.39 and 420.3+/-30.5 microg/l, respectively). The rhIGF-I administration did not affect mGHc in OB or NW (1.1+/-0.9 and 3.2+/-1.0 microg/l, respectively) but inhibited (P<0.05) the GH response to GHRH in OB (324.2+/-153.1 microg/l) and NW (730.2+/-288.1 microg/l). CONCLUSIONS: Our study shows that the administration of low dose rhIGF-I reduces the somatotroph responsiveness to GHRH in obesity as well as in normal subjects.

Adult↗
PubMed2001

Elderly subjects show severe impairment of dehydroepiandrosterone sulphate and reduced sensitivity of cortisol and aldosterone response to the stimulatory effect of ACTH(1-24).

OBJECTIVE: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in ageing has been reported both in humans and in animals and may be involved in age-related changes in body composition, structure functions and metabolism, as well as in brain ageing. Despite the supposed HPA hyperactivity and its refractoriness to negative glucocorticoid feedback, low levels of dehydroepiandrosterone (DHEA) and its sulphate have been clearly demonstrated in human ageing and may suggest another cause of age-related changes in structure function and metabolism. Thus, our aim was to verify the adrenal responsiveness to various ACTH doses in normal elderly subjects. DESIGN: We studied cortisol (F), aldosterone (A) and DHEA responses to the sequential administration of very low, low and supramaximal ACTH1-24 doses (0.06 microg or 0.5 microg followed by 250 microg ACTH1-24 i.v. at 0 and +60 minutes) in healthy elderly subjects (ES) [six females and two males, aged 63-75 years, body mass index (BMI) 22-26 kg/m2]. The results in ES were compared with those recorded in healthy young subjects (YS) (six females and six males, aged 22-34 years, BMI 20-25 kg/m2). RESULTS: Basal DHEA levels in ES were lower (P < 0.05) than in YS, while F and A levels were similar in both groups. DHEA, F and A responses to ACTH were dose-dependent in both groups. In ES, however, DHEA levels showed no response to the 0.06 microg dose, a modest increase after 0.5 microg and a clearer rise after 250 microg ACTH; at any dose, the DHEA response in ES was clearly lower than in YS (P < 0.04). The F responses to 0.5 microg and 250 microg ACTH in ES were similar to those in YS; whereas, in ES, 0.06 microg ACTH elicited a non significant F increase which was significantly lower than in YS (P < 0.05). Similarly, the A responses to the highest ACTH doses were similar in both groups but, in ES, 0.06 microg ACTH elicited no increase in A secretion, which was clearly lower than in YS (P < 0.03). CONCLUSIONS: Normal elderly subjects show severe reduction of DHEA response to a wide range of ACTH doses, in agreement with peculiar impairment of the activity of the adrenal reticularis zone in ageing. In contrast to young adults, elderly subjects also show no cortisol and aldosterone response to a very low ACTH dose. This evidence indicates a reduced sensitivity to ACTH in the fasciculata and glomerulosa zones of the adrenal gland in ageing.

Adult↗
PubMed2001

Effect of digoxin on the somatotroph responsiveness to growth hormone-releasing hormone (GHRH) alone or combined with arginine in normal young volunteers.

BACKGROUND: The activity of the GH/IGF-I axis, known to play a major role in myocardial structure and function, has been reported to be altered in patients with chronic heart failure. AIM AND DESIGN OF THE STUDY: In order to evaluate the possibility that clinically used cardioactive drugs may exert neuroendocrine influences on somatotroph secretion, we studied the effects of pretreatment with enalapril (20 mg/day orally for 3 days), furosemide (20 mg i.v. as a bolus at -5 minutes) or digoxin (0.25 mg orally 4x/day for 3 days) on the GH response to growth hormone-releasing hormone (GHRH) (1.0 microg/ kg i.v. as a bolus at 0 minutes) in 12 healthy male adults (age [mean +/- SEM] 30.2 +/- 1.4 years; BMI 22.7 +/- 0.7 kg/ m2). In a subgroup of 8 subjects the same study was performed testing the GH response to GHRH + arginine (ARG; 0.5 g/kg i.v. from 0 to + 30 minutes). RESULTS The GH response to GHRH (1,304.1 +/- 248-5 microg/l/h) was not modified by enalapril (1,368.7 +/- 171.2 microg/l/h) or by furosemide (1,269.3 +/- 185.2 microg/l/h) but was significantly blunted by digoxin (613.6 +/- 73.2 microg/l/h, P < 0.05). On the other hand digoxin, enalapril and furosemide did not modify the GH response to GHRH +ARG. CONCLUSIONS: Digoxin, but not enalapril or furosemide, inhibits the GH response to GHRH in normal subjects. The blunting effect of digoxin on the GHRH-induced GH response is counteracted by arginine. These findings show that digoxin possesses an inhibitory effect on somatotroph secretion that may be mediated at the hypothalamic level.

Adult↗