Neuroendocrine predictors of vasoplegia after cardiopulmonary bypass.

PURPOSE: Vasoplegia often complicates on-pump cardiac surgery. Systemic inflammatory response induced by extracorporeal circulation represents the major determinant, but adrenal insufficiency and postoperative vasopressin deficiency may have a role. Pathophysiological meaning of perioperative changes in endocrine markers of hydro-electrolyte balance has not still fully elucidated. Objectives of the present research study were to estimate the incidence of vasoplegia in a homogeneous cohort of not severe cardiopathic patients, to define the role of presurgical adrenal insufficiency, to evaluate copeptin and NT-proBNP trends in the perioperative. METHODS: We conducted a prospective cohort study in the cardiac intensive care unit of a tertiary referral center. We evaluated 350 consecutive patients scheduled for cardiac surgery; 55 subjects completed the study. Both standard and low-dose corticotropin stimulation tests were performed in the preoperative; copeptin and NT-proBNP were evaluated in the preoperative (T0), on day 1 (T1) and day 7 (T2) after surgery. RESULTS: Nine subjects (16.3%) developed vasoplegic syndrome with longer bypass and clamping time (p < 0.001). Reduced response to low-dose ACTH test was not associated to vasoplegia. Preoperative copeptin > 16.9 pmol/L accurately predicted the syndrome (AUC 0.86, 95% CI 0.73-0.94; OR 1.17, 95% CI 1.04-1.32). An evident correlation was observed at 7 days postoperative between NT-proBNP and copeptin (r 0.88, 95% CI 0.8-0.93; p < 0.001). CONCLUSION: Preoperative impaired response to low-dose ACTH stimulation test is not a risk factor for post-cardiotomic vasoplegia; conversely, higher preoperative copeptin predicts the complication. On-pump cardiac surgery could be an interesting model of rapid heart failure progression.

Multi-level and hybrid modelling approaches for systems biology.

During the last decades, high-throughput techniques allowed for the extraction of a huge amount of data from biological systems, unveiling more of their underling complexity. Biological systems encompass a wide range of space and time scales, functioning according to flexible hierarchies of mechanisms making an intertwined and dynamic interplay of regulations. This becomes particularly evident in processes such as ontogenesis, where regulative assets change according to process context and timing, making structural phenotype and architectural complexities emerge from a single cell, through local interactions. The information collected from biological systems are naturally organized according to the functional levels composing the system itself. In systems biology, biological information often comes from overlapping but different scientific domains, each one having its own way of representing phenomena under study. That is, the different parts of the system to be modelled may be described with different formalisms. For a model to have improved accuracy and capability for making a good knowledge base, it is good to comprise different system levels, suitably handling the relative formalisms. Models which are both multi-level and hybrid satisfy both these requirements, making a very useful tool in computational systems biology. This paper reviews some of the main contributions in this field.

Acute effects of acylated ghrelin on salbutamol-induced metabolic actions in humans.

The aim of this study is to describe a potential modulatory effect of acute acylated ghrelin (AG) administration on the glucose, insulin, and free fatty acids (FFA) responses to salbutamol (SALBU). Six healthy young male volunteers underwent the following four testing sessions in random order at least 7 days apart: (a) acute AG administration (1.0 µg/kg i.v. as bolus at 0'); (b) SALBU infusion (0.06 µg/kg/min i.v. from -15' to +45'); (c) SALBU infusion+AG; and (d) isotonic saline infusion. Blood samples for glucose, insulin, and FFA levels were collected every 15 min. As expected, with respect to saline, SALBU infusion induced a remarkable increase in glucose (10.8±5.6 mmol/l×min; P<0.05), insulin (2436.8±556.9 pmol/l×min; P<0.05), and FFA (18.9±4.5 mmol/l×min; P<0.01) levels. A significant increase in glucose (7.4±3.9 mmol/l×min; P<0.05) and FFA levels (10.0±2.8 mmol/l×min; P<0.01) without significant variations in insulin levels were recorded after AG administration. Interestingly, the hyperglycemic effect of AG appeared to be significantly potentiated during SALBU infusion (26.7±4.8 mmol/l×min; P<0.05). On the other hand, the stimulatory effect of SALBU on insulin and FFA was not significantly modified by AG administration. The results of this study show that acute AG administration has a synergic effect with ß2-adrenergic receptor activation by SALBU on blood glucose increase, suggesting that their pharmacological hyperglycemic action takes place via different mechanisms. On the other hand, AG has a negligible influence on the other pharmacological metabolic effects of SALBU infusion.

Impact of short-term treatment with benzodiazepines and imidazopyridines on glucose metabolism in healthy subjects.

AIM: In the last years there has been a progressive reduction of the average duration of sleep and an increase in the incidence of sleep disturbances. At the same time, an increase of the incidence of the metabolic syndrome has been described, partly attributable to the progressive worsening of dietary habits and the increase in sedentary lifestyle. Recent studies suggest that adequate sleep is essential to maintain good glucose metabolism and sleep disturbances may contribute to the manifestation of the metabolic syndrome. Benzodiazepines (BZ), such as brotizolam, and imidazopyridines, such as zolpidem, are frequently used as hypnotics but their potential impact on glucose metabolism has never been evaluated so far. METHODS: In 12 healthy volunteers [age (mean ± SEM) 38.3 ± 8.1 years; body mass index (BMI) 21.9 ± 0.8 kg/m²] we studied glucose and insulin responses to oral glucose tolerance test (OGTT, 75 g) before and after 15 days treatment with brotizolam 0.25 mg/day or zolpidem 10 mg/day. RESULTS: Brotizolam increased glucose delta area under curve response to the OGTT by 122 % (p < 0.01) and zolpidem by 86 % (p < 0.01) without significant variations of insulin levels, suggesting an impact on insulin sensitivity and/or insulin secretion. CONCLUSIONS: This study suggests that BZ and imidazopyridines have a rapid glucometabolic effect that is detectable as early as after 15 days treatment.

The GH-releasing effect of acylated ghrelin in normal subjects is refractory to GH acute auto-feedback but is inhibited after short-term GH administration inducing IGF1 increase.

OBJECTIVE: GH secretion is regulated by an interplay between GH-releasing hormone (GHRH), somatostatin (SST), and other central and peripheral signals. Acylated ghrelin (AG) amplifies GH pulsatility acting, at least partially, independently from GHRH and SST. The GH response to GHRH is inhibited by recombinant human GH (rhGH), likely due to a SST-mediated negative GH auto-feedback. The effect of exogenous rhGH on the GH-releasing effect of AG has never been tested. DESIGN AND METHODS: In six healthy volunteers, we studied the GH response to acute AG administration (1.0 µg/kg i.v.) during saline or rhGH infusion (4.0 µg/kg per h i.v.) or after 4-day rhGH (10.0 µg/kg s.c.) administration. RESULTS: Compared with saline, rhGH infusion increased GH levels (P<0.01). During saline, acute i.v. AG induced a marked increase (P<0.01) in GH levels similar to those observed after AG administration during rhGH infusion. During s.c. rhGH, IGF1 levels rose from day 0 to day 5 (P<0.01). After 4-day s.c. rhGH, i.v. AG increased (P<0.01) GH levels, though significantly (P<0.05) less than on day 0. CONCLUSIONS: The marked somatotroph-releasing effect of AG is refractory to a direct GH auto-feedback whereas is markedly inhibited after 4-day rhGH administration, suggesting the possibility of a selective IGF1-mediated inhibitory feedback.

Does use of metformin protect against cancer in Type 2 diabetes mellitus?

BACKGROUND: Type 2 diabetes mellitus has been associated with an increased cancer risk, which can be modified by specific hypoglycemic drugs. In particular, metformin, the most frequently prescribed biguanide, is now considered a protective agent against cancer incidence and mortality in Type 2 diabetic patients. AIMS: To review the potential associations between metformin use and cancer incidence and mortality and the possible biological links implicated in these associations. MATERIALS AND METHODS: We searched English-language original investigations published through September 2011. RESULTS: Metformin could block the mitogenic effects of insulin, but this effect does not entirely explain the reduction in cancer incidence. Metformin also plays a direct inhibition of cancer cell growth via the inhibitory effects of AMP-activated protein kinase on the mTOR pathway, which regulates cell growth and proliferation. Accordingly, many epidemiological studies have shown that metformin use is associated with a lower cancer incidence and mortality through a dose-response relationship, with greater exposure being associated with stronger risk reduction. Randomized clinical trials testing the effects of metformin on both recurrence and survival in early-stage breast cancer are on-going; these trials are based on pilot studies demonstrating an adjuvant effect of this drug in breast cancer. CONCLUSIONS: Metformin is an inexpensive and safe drug, that may modify the increased cancer risk of Type 2 diabetic patients. On-going clinical trials will show whether this drug can enhance the effect of chemotherapy in the treatment of cancer.

Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans.

OBJECTIVE: To clarify the metabolic effects of an overnight i.v. infusion of unacylated ghrelin (UAG) in humans. UAG exerts relevant metabolic actions, likely mediated by a still unknown ghrelin receptor subtype, including effects on ß-cell viability and function, insulin secretion and sensitivity, and glucose and lipid metabolism. DESIGN: We studied the effects of a 16-h infusion (from 2100 to 1300  h) of UAG (1.0  µg/kg per h) or saline in eight normal subjects (age (mean±s.e.m.), 29.6±2.4 years; body mass index (BMI), 22.4±1.7  kg/m(2)), who were served, at 2100 and 0800  h respectively, with isocaloric balanced dinner and breakfast. Glucose, insulin, and free fatty acid (FFA) levels were measured every 20  min. RESULTS: In comparison with saline, UAG induced significant (P<0.05) changes in glucose, insulin, and FFA profiles. UAG infusion decreased glucose area under the curve (AUC) values by 10% (UAG(0 - 960  min): 79.0±1.7×10(3)  mg/dl per min vs saline(0- 960  min): 87.5±3.8×10(3)  mg/dl per min) and the AUC at night by 14% (UAG(180)(-)(660  min): 28.4±0.5×10(3)  mg/dl per min vs saline(180 - 660  min): 33.2±1.1×10(3)  mg/dl per min). The overall insulin AUC was not significantly modified by UAG infusion; however, insulin AUC observed after meals was significantly increased under the exposure to UAG with respect to saline at either dinner or breakfast. The FFA AUC values were decreased by 52% under the exposure to UAG in comparison with saline (UAG(0 - 960  min): 0.3±0.02×10(3)  mEq/l per min vs saline(0 - 960  min): 0.6±0.05×10(3)  mEq/l per min). CONCLUSIONS: Exposure to the i.v. administration of UAG improves glucose metabolism and inhibits lipolysis in healthy volunteers. Thus, in contrast to the diabetogenic action of AG, UAG displays hypoglycemic properties.

The metabolic response to the activation of the beta-adrenergic receptor by salbutamol is amplified by acylated ghrelin.

BACKGROUND: It is well recognized that beta-adrenergic receptors mediate important endocrine and metabolic actions. In fact, beta-adrenergic receptor activation negatively influences GH secretion while exerting relevant metabolic actions such as the stimulation of insulin secretion, glycogenolysis, and lipolysis. AIM: We have already shown that the activation of the GH secretagogue receptor (GHS-R)-1a by acylated ghrelin (AG) counteracts the inhibitory effect of salbutamol (SALB), a beta2-adrenergic agonist, on GH release. The aim of the present study in humans was to clarify whether the metabolic response to SALB is affected by the infusion of AG, also known to exert significant metabolic actions. METHODS: Six healthy young male volunteers underwent the following testing sessions in random order at least 5 days apart: a) SALB (0.06 microg/kg/min iv from 0 to 60 min) alone; b) SALB in combination with AG (1.0 microg/kg/min iv from -60 to 60 min); c) isotonic saline. Insulin, glucose, and free fatty acids (FFA) levels were evaluated every 15 min. RESULTS: As expected, with respect to saline, SALB administration tended to increase both insulin secretion [Delta area under the curve (DeltaAUC): 0.16+/-0.09 vs 0.003+/-0.077 x 10(3) microU/ml/min; p>0.05] and FFA levels (DeltaAUC: 8.0+/-7.3 vs -4.0+/-4.0 mEq/l/min; p>0.05), while glucose levels did not change. The metabolic response to SALB was significantly modified under the exposure of AG. In fact, under AG infusion, SALB elicited a more marked increase of FFA (DeltaAUC: 22.3+/-3.2 vs 8.0+/-7.3 mEq/l/min; p<0.05) as well as a slight elevation in insulin (DeltaAUC: 0.37+/-0.11 vs 0.16+/-0.09 x 10(3) microU/ml/min; p>0.05). Under AG, the baseline glucose levels were more elevated but, again, in combination with AG, SALB did not significantly modify glucose levels. CONCLUSIONS: Beta-adrenergic receptors and AG are likely to interact at the metabolic level. In humans, the lypolitic response to a beta2-adrenergic agonist such as SALB is amplified by AG. Meanwhile, during the co-treatment, the marginal insulinotropic effect was not associated with an increase in glycemia.

Circulating obestatin levels in normal and Type 2 diabetic subjects.

BACKGROUND: Obestatin has been discovered as a new product of the ghrelin gene. Its physiological actions are still a matter of debate, but it seems that this peptide is likely to be involved in the control of insulin secretion and action as well as of adipocyte function. It has been already shown that obestatin secretion in humans is negatively modulated by food intake. AIM: To clarify obestatin secretion in normal subjects and in patients with Type 2 diabetes (T2D) in basal conditions and after a standardized meal. SUBJECTS/METHODS: Five normal subjects and 5 T2D patients were studied during infusion of saline (iv for over 5 h from -120 to +180 min). A standardized lunch was served at 0 min. Obestatin, glucose, and insulin levels were assayed at -120, -90, -60, -45, -30, -15, 0, 15, 30, 45, 60, 90, 120, 150, and 180 min. RESULTS: From -120 to 0 min, obestatin levels in normal and T2D subjects were similar (area under the curve: 32.3+/-5.6 pg/ml/min vs 31.1+/-1.0 pg/ml/min). After the meal, circulating obestatin levels underwent a clear decrease in normal subjects (0 min: 300.6+/-34.7 pg/ml vs nadir at 60 min: 161.8+/-29.4 pg/ml; p=0.002) but not in diabetic patients (0 min: 267.2+/-16.5 pg/ml vs nadir at 180 min: 226.0+/-10.5 pg/ml). CONCLUSION: This study shows that normal and diabetic subjects display similar levels of circulating obestatin in fasting condition. However patients with T2D look refractory to the inhibitory effect of meal on obestatin secretion.

Metabolic and cardiovascular profile in patients with Addison's disease under conventional glucocorticoid replacement.

OBJECTIVE: Although two studies have shown that Addison's disease (AD) is still a potentially lethal condition for cardiovascular, malignant, and infectious diseases, a recent retrospective study showed a normal overall mortality rate. Differently from secondary hypoadrenalism, scanty data exist on the role of conventional glucocorticoid replacement on metabolic and cardiovascular outcome in AD. SUBJECTS AND METHODS: In 38 AD under conventional glucocorticoid replacement (hydrocortisone 30 mg/day or cortisone 37.5 mg/day) ACTH, plasma renin activity (PRA), DHEAS, fasting glucose and insulin, 2-h glucose after oral glucose tolerance test, serum lipids, 24-h blood pressure and intima-media thickness (IMT) were evaluated and compared with 38 age-, sex- and body mass index (BMI)-matched controls (CS). RESULTS: AD had ACTH and PRA higher and DHEAS lower (p<0.0005) than CS. Mean waist was higher (p<0.05) in AD than in CS. Although no differences were found for mean gluco-lipids levels, a higher percentage of AD compared to CS were IGT (8 vs 0%), hypercholesterolemic (18 vs 8%), and hypertriglyceridemic (18 vs 8%); none of the AD and CS showed either HDL<40 mg/dl or LDL>190 mg/dl. At the multiple regression analysis, in both AD and CS, BMI was the best predictor of 2-h glucose and age of total and LDL cholesterol; in AD, no significant correlation was found between the above mentioned metabolic parameters and either hormone levels or disease duration. In both AD and CS 24-h blood pressure and IMT were normal. CONCLUSIONS: Our study shows a higher prevalence of central adiposity, impaired glucose tolerance and dyslipidemia in AD patients.

Beta-adrenergic agonism does not impair the GH response to acylated ghrelin in humans.

BACKGROUND: Acylated ghrelin (AG) is a physiological GH secretion amplifier, in part stimulating GHRH neurones and antagonizing somatostatin activity. In humans, AG is one of the most potent pharmacological stimuli of GH secretion and, unlike GHRH, is refractory to the inhibitory effect of glucose, free fatty acids (FFA) and somatostatin. Somatotroph secretion is also profoundly modulated by the adrenergic system. Indeed, beta-adrenergic agonists abolish spontaneous and GHRH-stimulated GH secretion. Based on these data, the aim of the present study was to investigate the effects of beta adrenergic agonism on the GH response to AG. SUBJECTS AND MEASUREMENTS: Six young healthy male volunteers underwent: (a) acute AG intravenous (iv) administration (1.0 microg/kg); (b) salbutamol infusion (SLB; 0.06 microg/kg/min iv); (c) AG + SLB; and (d) saline infusion. In all sessions GH levels were assayed every 15 min from time -30 to +210 min. RESULTS: SLB induced a significant (P < 0.05) inhibition of spontaneous GH secretion that persisted up to 75 min after SLB withdrawal. AG induced a marked increase (P < 0.01) in GH that was not modified by SLB. CONCLUSIONS: The GH-releasing effect of AG is refractory to the inhibitory effect of SLB-induced beta-adrenergic receptor activation. Although further studies are needed to confirm these results during the lifespan and particularly during prolonged exposure to beta agonists, the present data clearly suggest that, among GH stimulatory tests, AG administration might be the most suitable in clinical conditions of chronic treatment with beta-2 agonists, such as in asthmatic disease.

Cortistatin-8, a synthetic cortistatin-derived ghrelin receptor ligand, does not modify the endocrine responses to acylated ghrelin or hexarelin in humans.

Cortistatin (CST), a neuropeptide with high structural homology with somatostatin (SST), binds all SST receptor (SST-R) subtypes but, unlike SST, also shows high binding affinity to ghrelin receptor (GHS-R1a). CST exerts the same endocrine activities of SST in humans, suggesting that the activation of the SST-R might mask the potential interaction with ghrelin system. CST-8, a synthetic CST-analogue devoid of any binding affinity to SST-R but capable to bind the GHS-R1a, has been reported able to exert antagonistic effects on ghrelin actions either in vitro or in vivo in animals. We studied the effects of CST-8 (2.0 microg/kg i.v. as a bolus or 2.0 microg/kg/h i.v. as infusion) on both spontaneous and ghrelin- or hexarelin- (1.0 microg/kg i.v. as bolus) stimulated GH, PRL, ACTH and cortisol secretion in 6 normal volunteers. During saline, no change occurred in GH and PRL levels while a spontaneous ACTH and cortisol decrease was observed. As expected, both ghrelin and hexarelin stimulated GH, PRL, ACTH and cortisol secretion (p<0.05). CST-8, administered either as bolus or as continuous infusion, did not modify both spontaneous and ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. In conclusion, CST-8 seems devoid of any modulatory action on either spontaneous or ghrelin-stimulated somatotroph, lactotroph and corticotroph secretion in humans in vivo. These negative results do not per se exclude that, even at these doses, CST-8 might have some neuroendocrine effects after prolonged treatment or that, at higher doses, may be able to effectively antagonize ghrelin action in humans. However, these data strongly suggest that CST-8 is not a promising candidate as GHS-R1a antagonist for human studies to explore the functional interaction between ghrelin and cortistatin systems.

Ankle brachial pressure index usefulness as predictor factor for coronary heart disease in diabetic patients.

Ankle brachial pressure index (ABPI) is a non-invasive marker of atherosclerosis, helpful to identify subjects at high-risk for coronary heart disease (CHD) among large populations with cardiovascular disease (CVD) risk factors. The diagnostic role of ABPI has been also recognized in patients with diabetes. In the present study, the role of an ABPI score < 0.90 in predicting CHD has been evaluated in a large series of patients with Type 2 diabetes mellitus and compared to other known CVD risk factors. Nine hundred and sixty-nine (mean age was 66.1 yr) consecutive patients with Type 2 diabetes mellitus were evaluated. The patients were followed-up for 18.3+/-5.2 months (range 12- 24) and all events of CHD, defined as myocardial infarction, unstable and resting angina or coronary atherosclerosis at the instrumental investigation (at the coronary angiography and/or perfusion stress testing) were recorded. A rate of 17.5% of CHD events were recorded in diabetic population during the follow-up period. The relative risk of CHD was significantly increased for male patients [odds ratio (OR): 1.6; 95% confidence interval (CI): 1.1-2.2], patients with age > or = 66 yr (OR: 1.8; 95% CI: 1.3-2.5), body mass index (BMI) > 30 (OR: 1.5; 95% CI: 1.1-2.1), waist circumference > 88 cm for females and 102 cm for males (OR: 1.5; 95% CI: 1.0-2.1), proteinuria > or = 30 microg per min (OR: 1.6; 95% CI: 1.1-2.3), LDL-cholesterol > or = 100 mg/dl (OR: 2.1; 95% CI: 1.5-3.0), glycated hemoglobin > 7% (OR: 1.6; 95% CI: 1.1-2.3), insulin therapy (OR: 1.9; 95% CI: 1.3-2.9), and ABPI < 0.90 (OR: 3.7; 95% CI: 2.2- 6.2). BMI was higher in patients with ABPI < 0.90 than in those with ABPI > or = 0.90 (p<0.05). At the multivariate analysis, ABPI < 0.90 was the best factor independently associated with CHD (p<0.001). APBI < 0.90 is strongly associated to CHD in Type 2 diabetic patients. We recommend to use ABPI in diabetic patients and to carefully monitor diabetic subjects with an ABPI lower than 0.90.

Is TW3 height prediction more accurate than TW2? Preliminary data.

BACKGROUND/AIMS: Skeletal maturation is considered a reliable variable in evaluating the 'tempo' of growth. It is important in the diagnosis of endocrinological diseases, in chronic diseases, in hormonal therapy follow-up and in computing height prediction for prognostic and therapeutic purposes. It is also used when chronological age is not available for minors without known birth dates. There are different methods to evaluate skeletal maturation and height prediction. The Tanner-Whitehouse (TW) method 2 (TW2) has been considered to be the most useful method so far, and has recently been updated with modified height prediction equations (TW2-Mark II). TW3 is the newest method. The aim of this study is to evaluate whether TW3 is more accurate in the assessment of height prediction than TW2-Mark II in a sample of healthy north Italian subjects. METHODS: Anthropometrical data were collected as part of a survey in 1977-1978 in Turin. The sample involved 1,384 healthy children. The children, now adults, have been traced and recalled to measure their final height in order to test height prediction reliability. At present, we have collected 118 adult heights. RESULTS: According to the TW2 method 40% of the males had a height prediction error larger than +/- residual SD (4.1 cm), and with TW3 this was 32.9%. The female height prediction error with TW2 was larger than +/- residual SD (3.6 cm) in 29.2% of girls, and the same value was found with TW3. CONCLUSION: According to our preliminary data, TW3 does not represent any real progress.

d-Lys-GHRP-6 does not modify the endocrine response to acylated ghrelin or hexarelin in humans.

Acylated ghrelin exerts numerous endocrine and non-endocrine activities via the GH Secretagogue receptor type 1a (GHS-R1a). D-Lys-GHRP-6 has been widely studied in vitro and in vivo in animal studies as GHS-R1a antagonist; its action in humans has, however, never been tested so far. Aim of our study was to verify the antagonistic action of D-Lys-GHRP-6 on the endocrine responses to acylated ghrelin and hexarelin, a peptidyl synthetic GHS, in humans. The effects of different doses of D-Lys-GHRP-6 (2.0microg/kg iv as bolus or 2.0microg/kg/h iv as infusion) on both spontaneous and acylated ghrelin- or hexarelin (1.0microg/kg iv as bolus) -stimulated GH, PRL, ACTH and cortisol levels were studied in six normal volunteers (age [mean+/-SEM]: 25.4+/-1.2yr; BMI: 22.3+/-1.0kg/m(2)). The effects of D-Lys-GHRP-6 (2.0microg/kg iv as bolus+4.0microg/kg/h iv) on the GH response to 0.25microg/kg iv as bolus acylated ghrelin was also studied. During saline, spontaneous ACTH and cortisol decrease was observed while non changes occurred in GH and PRL levels. Acylated ghrelin and hexarelin stimulated (p<0.05) GH, PRL, ACTH and cortisol secretions. D-Lys-GHRP-6 administered either as bolus or a continuous infusion did not modify both spontaneous and acylated ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. D-Lys-GHRP-6 did not modify even the GH response to 0.25microg/kg iv acylated ghrelin. In conclusion, D-Lys-GHRP-6 does not affect the neuroendocrine response to both ghrelin and hexarelin. These findings question D-Lys-GHRP-6 as an effective GHS-R1a antagonist for human studies.

Ghrelin: endocrine, metabolic and cardiovascular actions.

Ghrelin is a peptide predominantly produced by the stomach, although expressed by many other tissues, including the pancreas and the cardiovascular system. Its secretion is negatively associated to body mass index and undergoes fluctuations during the day. It is stimulated by energy restriction and acetylcholine, while it is reduced by gastrectomy, food intake, glucose, insulin and SRIF. Ghrelin is a natural ligand of the GH secretagogue (GHS) receptor 1a (GHS-R1a), known being specific for synthetic GHS. GHS-R1a expression and binding studies showed GHS-R in the hypothalamus-pituitary area but also in other brain areas as well as in peripheral, endocrine and non-endocrine tissues, including the pancreas and the cardiovascular system. Besides its potent GH-releasing effect, ghrelin: 1) stimulates lactotroph and corticotroph secretion while it negatively modulates the gonadal axis; 2) exerts central actions including orexigenic effect coupled with control of energy expenditure; 3) influences either the exocrine or the endocrine pancreatic function and the glucose and lipid metabolism; 4) controls gastric motility and acid secretion; 5) exerts cardiovascular actions; 6) modulates cell proliferation. Ser3-acylation of ghrelin is essential for binding the GHS-R1a and for its endocrine actions. However, both non-acylated and acylated ghrelin are bound by GHS-R subtypes at both the pancreatic and the cardiovascular level. Non-acylated ghrelin is not an inactive peptide; it exerts some non-endocrine actions such as cardiovascular activities, modulation of cell proliferation and even some metabolic action such as modulation of insulin secretion, glucose and lipid metabolism. Notably, some GHS-R subtypes are not ghrelin receptors; cardiovascular receptors specific for peptidyl GHS have been found and it has been shown they mediate some specific actions that are not shared by ghrelin.

Cortistatin-17 and -14 exert the same endocrine activities as somatostatin in humans.

Cortistatin (CST) is a neuropeptide, which binds with high affinity all somatostatin (SS) receptor subtypes and shows high structural homology with SS itself. A receptor specific for CST only, i.e., not recognized by SS, has been recently described in agreement with data reporting that not all CST actions are shared by SS. Interestingly, CST but not SS also binds ghrelin receptor (GHS-R1a) in vitro, suggesting a potential interplay between CST and ghrelin system. The aim of this study was to investigate in humans the endocrine and metabolic activities of human CST-17 in comparison with rat CST-14 that has previously been shown to exert the same endocrine actions of SS in healthy volunteers. To this aim, in six healthy male volunteers (age [median, 3rd-97th centiles]: 28.5; 23.6-34.3 years; Body Mass Index: 23.5; 21.0-25.1 kg/m(2)), we studied the effects of human CST-17 (2.0 microg/kg/h iv over 120 min), rat CST-14 (2.0 microg/kg/h iv over 120 min) and SS-14 (2.0 microg/kg/h iv over 120 min) on: (a) spontaneous GH, ACTH, PRL, cortisol, insulin and glucose levels; (b) the GH responses to GHRH (1.0 microg/kg iv at 0 min); (c) the GH, PRL, ACTH, cortisol, insulin and glucose responses to ghrelin (1.0 microg/kg iv at 0 min). CST-17 inhibited (p < 0.01) basal GH secretion to the same extent of CST-14 and SS-14. Spontaneous PRL, ACTH and cortisol secretion were not significantly modified by CST-17, CST-14 or SS-14. CST-17 as well as CST-14 and SS-14 also inhibited (p < 0.05) spontaneous insulin secretion to a similar extent. None of these peptides modified glucose levels. The GH response to GHRH was inhibited to the same extent by CST-17 (p < 0.01), CST-14 (p < 0.01) and SS-14 (p < 0.05 ). The ghrelin-induced GH response was higher than that elicited by GHRH (p < 0.01) and inhibited by CST-17 (p < 0.05) as well as by CST-14 (p < 0.05) and SS-14 (p < 0.01). The PRL, ACTH and cortisol responses to ghrelin were unaffected by CST-17, CST-14 or SS-14. On the other hand, the inhibitory effect of ghrelin on insulin levels was abolished by CST-17, CST-14 or SS-14 (p < 0.05) that, in turn, did not modify the ghrelin-induced increase in glucose levels. In conclusion, this study demonstrates that human CST-17 and rat CST-14 exert the same endocrine activities of SS in humans. The endocrine actions of human and rat CST therefore are likely to reflect activation of classical SS receptors.

Platelet cGMP inversely correlates with age in healthy subjects.

Biochemical modifications associated with the increase in platelet activity with age are not well defined. Furthermore it is well known that the nitric oxide/cyclic 3', 5'-guanosine monophosphate (cGMP) pathway regulates platelet aggregation. The aim of the present study was to examine the relationship between platelet content of cGMP and age. 120 normal subjects, evaluating the cGMP platelet concentration, 17betaE2, IGF-I, dehydroepiandrosterone sulphate (DHEAS), insulin, plasma glucose, lipid pattern, homocysteine and PAI-I antigen, were studied. The multivariate analysis in a model with cGMP as dependent variable and with age, LDL, apolipoprotein B (ApoB), DHEAS, E2 and insulin-like growth factor (IGF)-I as independent variables shows a negative correlation between cGMP and age (p<0.01, beta=-0.388). In conclusion our data suggest that the reduced efficiency of the system constitutive nitric oxide synthase (cNOS)/guanylate cyclase represents at least one of the reasons of the increased platelet aggregability with age.