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Sleep disturbances may be associated with impaired glucose metabolism . The aim of this study was to evaluate sleep duration and quality in relation to glycemic control in patients with type 2 diabetes. In a cross-sectional study, sleep duration and quality were assessed in 47 middle-aged patients with type 2 diabetes treated with oral agents and without sleep disturbing complications and 23 healthy control subjects similar by age, sex, body mass index, occupation and schooling. Sleep was recorded by wrist-actigraphy for three consecutive days under free-living conditions. Univariate analysis showed lower sleep maintenance ( P = 0.002) and sleep efficiency ( P = 0.005), and higher fragmentation index ( P < 0.0001), total activity score ( P = 0.05) and moving time ( P < 0.0001) in patients with type 2 diabetes. After adjusting for age, gender and schooling, fragmentation index and moving time remained significantly higher in the patients with diabetes ( P < 0.05, both). HbA1c correlated inversely with sleep efficiency ( r = −0.29; P = 0.047) and positively with moving time ( r = 0.31; P = 0.031). These findings suggest that type 2 diabetes is associated with sleep disruptions even in the absence of complications or obesity. The relevance of sleep abnormalities to metabolic control and possible strategies to improve sleep quality in type 2 diabetes deserve further investigation. [ABSTRACT FROM AUTHOR]

Ghrelin, an acylated peptide produced predominantly by the stomach, has been discovered to be a natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a). Ghrelin has recently attracted considerable interest as a new orexigenic factor. However, ghrelin exerts several other neuroendocrine, metabolic and also nonendocrine actions that are explained by the widespread distribution of ghrelin and GHS-R expression. The likely existence of GHS-R subtypes and evidence that the neuroendocrine actions, but not all the other actions, of ghrelin depend on its acylation in serine-3 revealed a system whose complexity had not been completely explored by studying synthetic GHS. Ghrelin secretion is mainly regulated by metabolic signals and, in turn, the modulatory action of ghrelin on the control of food intake and energy metabolism seems to be among its most important biological actions. However, according to a recent study, ghrelin-null mice are neither anorectics nor dwarfs and this evidence clearly depicts a remarkable difference from leptin null mice. Nevertheless, the original and fascinating story of ghrelin, as well as its potential pathophysiological implications in endocrinology and internal medicine, is not definitively cancelled by these data as GHS-R1a null aged mice show significant alterations in body composition and growth, in glucose metabolism, cardiac function and contextual memory. Besides potential clinical implications for natural or synthetic ghrelin analogues acting as agonists or antagonists, there are several open questions awaiting an answer. How many ghrelin receptor subtypes exist? Is ghrelin‘the’ or just‘a’ GHS-R ligand? That is, are there other natural GHS-R ligands? Is there a functional balance between acylated and unacylated ghrelin forms, potentially with different actions? Within the next few years suitable answers to these questions will probably be found, making it possible to gain a better knowledge of ghrelin's potential clinical perspectives. [ABSTRACT FROM AUTHOR]

Ghrelin, a 28-amino acid acylated peptide predominantly produced by the stomach, displays strong GH-releasing activity mediated by the hypothalamic-pituitary GH secretagogues (GHS) receptors (GHS-R) which had been shown specific for a family of synthetic, orally active molecules known as GHS. However, ghrelin and GHS, acting on central and peripheral receptors, also exert other actions. These include influence on pituitary functions, orexigenic action, influence on exocrine and endocrine gastro-entero-pancreatic functions, cardiovascular and anti-proliferative effects. In particular, the effect of ghrelin in promoting food intake and modulating energy metabolism strongly suggested that ghrelin has a key role in managing the neuroendocrine and metabolic response to starvation and that could be involved in the pathogenesis and/or in the metabolic and neuro-hormonal alterations of obesity and eating disorders. Although specific alterations in ghrelin secretion and/or action in obesity and anorexia nervosa (AN) have already been reported, the possibility that ghrelin analogues acting as agonists or antagonists has clinical perspectives for treatment of eating disorders presently remains a dream. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Ghrelin, a gastric-derived natural ligand of the GH secretagogue (GHS)-receptor (GHS-R), strongly stimulates GH secretion but also possesses other neuroendocrine actions, stimulates food intake and modulates the endocrine pancreas and energy homeostasis. Ghrelin secretion is negatively modulated by food intake. Similarly, glucose and also insulin probably exert an inhibitory effect on ghrelin secretion. Fasting ghrelin levels are reduced in obesity, elevated in anorexia nervosa and restored by weight recovery. The chronic elevation of circulating ghrelin levels in anorexia suggested the hypothesis of an alteration of the sensitivity to the orexigenic action of ghrelin in this condition. The aim of this study was to define the endocrine actions of ghrelin in patients with anorexia nervosa. DESIGN: We enrolled nine women with anorexia nervosa of restricter type [AN; age (mean ± SEM) 24.2 ± 1.8 years; body mass index (BMI) 14.7 ± 0.4 kg/m²] and seven normal young women in their early follicular phase as control group (NW; age 30.6 ± 3.1 years; BMI 20.3 ± 0.5 kg/m²). MEASUREMENTS: In all the subjects we studied the GH, PRL, ACTH, cortisol, insulin and glucose responses to acute ghrelin administration (1.0 μg/kg as i.v. bolus). The GH response to GHRH (1.0 μg/kg as i.v. bolus) and basal ghrelin and IGF-I levels were also evaluated in all the subjects. RESULTS Basal morning ghrelin and GH levels in AN (643.6 ± 21.3 ng/l and 10.4 ± 0.5 μg/l, respectively) were higher ( P < 0.05) than in NW (233.5 ± 14.2 ng/ l and 0.7 ± 0.7 μg/l, respectively). However, IGF-I levels in AN (145.3 ± 10.9 μg/l) were lower ( P < 0.05) than in NW (325.4 ± 12.6 μg/l). The GH response to GHRH in AN was higher ( P < 0.05) than that in NW, but in AN the GH response to ghrelin was lower ( P < 0.05) than that in NW. In AN and NW ghrelin also induced similar increases ( P < 0.05) in PRL, ACTH and cortisol levels. Ghrelin administration was followed by significant increase in glucose levels in NW ( P < 0.05) but not in AN. CONCLUSIONS: This study demonstrates that anorexia nervosa, a clinical condition of ghrelin hypersecretion, shows a specific reduction in the GH response to ghrelin, despite the hyper-responsiveness to GHRH administration. The impaired GH response to ghrelin in anorexia nervosa agrees with previous evidence of blunted GH response to synthetic GH secretagogues and could reflect desensitization of the GHS receptor induced by the chronic elevation of ghrelin levels in this pathological state. [ABSTRACT FROM AUTHOR]

Ghrelin, a 28 amino acid-acylated peptide predominantly produced by the stomach, displays strong growth hormone (GH)-releasing activity. It is mediated by the hypothalamic-pituitary GH secretagogue (GHS) receptors, which are specific to a family of synthetic, orally active molecules known as GHSs. However, despite their potent and reproducible GH-releasing activity, the potential clinical use of GHSs as orally active growth-promoting agents or anabolic anti-aging drugs has not been confirmed. Ghrelin and GHSs also exert other actions mediated through central and peripheral receptors, including stimulation of adrenocorticotrophic hormone and prolactin secretion, influence on insulin secretion and glucose metabolism, orexigenic effects and modulatory activity on the neuroendocrine and metabolic response to starvation, influence on exocrine gastro-entero-pancreatic functions, cardiovascular effects and modulation of cell proliferation and apoptosis. The discovery of ghrelin and the characterization of these GH-independent biological activities has widened the knowledge of some critical aspects of neuroendocrinology and suggests possible roles for GHSs and ghrelin in the treatment of pathophysiological conditions, including those unrelated to disorders of GH secretion. [ABSTRACT FROM AUTHOR]

According to the somatomedin model, growth hormone (GH)-dependent hepatic synthesis is responsible for maintaining circulating insulin-like growth factor (IGF)-I levels. On the other hand, the local autocrine/paracrine IGF-I expression in peripheral tissue is generally GH-independent and reflects the effects of various and tissue-specific trophic hormones. Circulating IGF-I levels undergo important age-related variations increasing at puberty and decreasing, thereafter, to low levels in the elderly. Low IGF-I levels in the elderly mainly reflect impaired somatotroph secretion but the decline in gonadal sex steroid levels, some protein and micronutrients malnutrition as well as age-dependent variations in IGF-binding proteins may also play a role in the age-related decrease in IGF-I activity. This, in turn, partially accounts for age-related changes in bones, muscles, cardiovascular system, central nervous system and the immune system. However, it is currently unclear whether treatment with exogenous IGF-I can retard or reverse age-related changes in body structure and function. [ABSTRACT FROM AUTHOR]

Aim: To investigate acute cardiotropic activities of hexarelin in patients with severe left ventricular dysfunction due to ischemic (iCMP) and dilated cardiomyopathy (dCMP). Methods and results: We studied the effect of intravenous hexarelin administration on growth hormone (GH) levels and left ventricular ejection fraction (LVEF) evaluated by radionuclide angiography in eight patients with dCMP (age 53.0±2.8, LVEF 16.7±2.1%) and five patients with iCMP (age 52.0±2.8 years, LVEF 22.6±2.1). Results were compared with a group of seven normal subjects (age 37.4±3.4 years, LVEF 64.0±1.5%) and seven patients with severe growth-hormone deficiency (GHD; age 42.0±4.4 years, LVEF 50.0±1.9%) previously studied with the same methodology. In dCMP and iCMP patients hexarelin induced a similar significant (P<0.05) increase in GH levels. In iCMP patients hexarelin induced a LVEF increase (peak LVEF 26.2±2.5%, P<0.05) as observed in normals and GHD, while in dCMP LVEF was unchanged (peak LVEF 17.7±1.7, P=NS). In all groups other hemodynamic parameters were unchanged. Conclusions: Acute hexarelin administration increases LVEF in iCMP patients (as in normals and GHD) but not in dCMP patients in spite of a similar GH releasing effect and basal LVEF. A possible explanation of the positive inotropic effect of hexarelin in iCMP could be a direct stimulation on viable myocardium or myocardial contractile reserve. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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 &bgr;-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 &mgr;g/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/m2), 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% (UAG0-960 min: 79.0±1.7×103 mg/dl per min vs saline0-960 min: 87.5±3.8×103 mg/dl per min) and the AUC at night by 14% (UAG180-660 min: 28.4±0.5×103 mg/dl per min vs saline180-660 min: 33.2±1.1 ×103 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 (UAG0-960 min: 0.3±0.02×103 mEq/l per min vs saline0-960 min: 0.6±0.05times;103 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. [ABSTRACT FROM AUTHOR]

Background Impaired GH secretion is a common finding in patients with primary hyperparathyroidism (PHP). Ghrelin displays strong GH-releasing action, mainly at the hypothalamic level. Objective To evaluate secretory response of GH to ghrelin in PHP patients. Patients Fifteen patients [11 women/4 men, mean age 54 years, range 32–70 years, body mass index (BMI) 25·0 ± 0·7 kg/m2] affected with PHP due to single parathyroid adenoma and 35 normal age-matched subjects (23 women/12 men, mean age 58 years, range 35–68 years, BMI 24·1 ± 1·1 kg/m2). Methods A measure of 1 µg/kg body weight i.v. acylated ghrelin or 1 µg/kg body weight i.v. GH releasing hormone (GHRH) followed by 0·5 g/kg body weight i.v. arginine (ARG) hydrochloride were administered to all subjects on alternate days in order to evaluate GH response. Results Mean serum GH peak after GHRH + ARG was 32·6 ± 7·8 and 17·4 ± 4·0 µg/l, in controls and PHP patients, respectively (P < 0·05). Mean serum GH peak after ghrelin was 70·4 ± 31·5 and 16·8 ± 1·9 µg/l, in controls and PHP patients, respectively, (P < 0·001). Using ROC curves, a serum GH peak > 22 µg/l after ghrelin stimulation might be considered as a cut-off value for identifying normal subjects. Ten (67%) PHP patients have impaired GH response to GHRH + ARG and 13 (87%) to ghrelin. Serum GH peak after ghrelin or GHRH + ARG was unrelated to serum IGF-1, PTH or ionized calcium concentrations. Conclusions The present data confirm that GH secretion is impaired in PHP patients using the potent GH secretagogue ghrelin and suggest that impaired GH secretion is likely due to a deleterious effect of hypercalcaemia at the hypothalamic level in PHP patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: The nutritional control of ghrelin has not been fully clarified yet. Particularly, the influence of aminoacids and lipids is controversial and, moreover, whether the intraluminal gastric contact with nutrients is required or if the modulatory action of nutrients on ghrelin secretion is mediated by insulin is still matter of debate. AIM OF THE STUDY: To clarify the role of nutrients in the control of ghrelin secretion evaluating the effects of intravenous and oral lipids and aminoacids compared with glucose and fructose load in healthy subjects. METHODS: A total of 6 healthy overnight-fasted volunteers underwent the following testing sessions: (a) iv arginine (ARG, 0.5 g/kg); (b) oral protein load (PRO, 50 g); (c) iv lipid-heparin infusion (Li He, Intralipid 10% 250 ml); (d) oral fat load (OIL, soy oil 40 g); (e) oral glucose load (OGL, 100 g); (f) oral fructose load (OFL, 100 g); (g) iv saline (SAL, 3 ml); (h) oral water load (WL, 200 ml). Total ghrelin, insulin, and glucose were assayed every 15 min from 0 up to +180 min. RESULTS: WL and SAL did not modify insulin, glucose and ghrelin. ARG induced a prompt but transient increase (P < 0.05) of insulin and glucose (P < 0.01), without modifying ghrelin secretion. PRO induced a mild but sustained increase of insulin secretion (P < 0.05) without affecting glucose and ghrelin. Li-He progressively increased circulating glucose (P < 0.01) without modifying insulin and ghrelin secretion. No significant variations in circulating glucose, insulin, and ghrelin occurred after OIL. OGL significantly (P < 0.01) increased insulin and glucose levels and progressively decreased (P < 0.05) ghrelin levels. OFL induced a mild (P < 0.05) increase of insulin without modifying glucose levels. Similarly, OFL was followed by a milder decrease (P < 0.05) of ghrelin levels. CONCLUSIONS: Differently from carbohydrates and independently from their modulatory effect on insulin secretion and glucose levels, both lipids and aminoacids play a negligible role in the acute control of ghrelin secretion either after acute enteral and parenteral administration. [ABSTRACT FROM AUTHOR]

Objective The presence of both the GH secretagogue (GHS) receptor and ghrelin in the pancreas indicates an involvement of this hormone in glucose metabolism. Ghrelin secretion is increased by fasting and energy restriction, decreased by food intake, glucose load, insulin and somatostatin in normal adults; however, food intake is not able to inhibit circulating ghrelin levels in children, suggesting that the profile of ghrelin secretion in children is different from that in adults. Moreover, how ghrelin secretion is regulated in childhood as a function of fat mass is still unclear. Design and subjects We studied the effect of oral glucose load (75 g solution orally) on circulating total ghrelin levels in 14 obese children (group A, four boys and 10 girls, aged 9·3 ± 2·3 years) and 10 lean children (group B, five boys and five girls, aged 9·7 ± 3·8 years). Measurements In all the sessions, blood samples were collected every 30 min from 0 up to +120 min. GH, insulin and glucose levels were assayed at each time point. Results Glucose peaks following an oral glucose tolerance test (OGTT) in groups A and B were similar; however, both basal and OGTT-stimulated insulin levels in group A were higher than in group B ( P < 0·05). Basal total ghrelin levels in group A (281·3 ± 29·5 pg/ml) were lower ( P < 0·0005) than in group B (563·4 ± 81·5 pg/ml). In both groups A and B, the OGTT inhibited total ghrelin levels ( P < 0·005). In terms of absolute values, total ghrelin levels in group A were lower ( P < 0·0005) than those in group B at each time point after glucose load. The percentage nadir in total ghrelin levels recorded in group A (−25% at 90 min) was similar to that recorded in group B (−31% at 120 min). Total ghrelin levels were negatively associated with BMI ( r = 0·5, P < 0·005) but not with glucose or insulin levels. Conclusion Ghrelin secretion is reduced in obese children. It is, however, equally sensitive in both obese and lean children to the inhibitory effect of oral glucose load. [ABSTRACT FROM AUTHOR]

Summary: Ghrelin is generally influenced by energy balance status and is inversely associated with body mass index (BMI), being reduced in simple obesity, notable exception being Prader Willi syndrome, and elevated in several conditions of undernutrition, including anorexia nervosa (AN). Interestingly, ghrelin levels have also been found elevated in patients with bulimia nervosa (BN) in spite of normal BMI. In humans, intravenous (iv) ghrelin administration induces endocrine (increase in GH, PRL, ACTH and cortisol) and metabolic (increase in glucose and decrease in insulin) effects as well as an increase in appetite and food intake. In AN, ghrelin administration surprisingly leads to a decreased GH response and absence of glycemic variations but normal PRL, ACTH and insulin response. This pattern would reflect a decrease in sensitivity to ghrelin or, alternatively, the metabolic status of AN. To further clarify the function of ghrelin in eating disorders, the endocrine and metabolic response to acute iv ghrelin (1.0μg/kg) was studied in seven young women with purging BN (BW, BMI, mean±SEM: 20.3±0.5kg/m2). Circulating total ghrelin levels were also measured. The results in BW were compared to those recorded in a group of nine healthy women (HW; BMI 22.3±2.5kg/m2). The GH response to ghrelin in BW overlapped with that in HW. Ghrelin administration also led to a similar increase in PRL, ACTH, cortisol and glucose levels in the two groups. Insulin levels were not significantly modified by ghrelin administration in either group. The overlapping endocrine and metabolic response to ghrelin in the two groups occurred with regard to circulating total ghrelin levels which were higher in BW than in HW. In conclusion, BN, a condition of ghrelin hypersecretion, is connoted by a normal endocrine and metabolic response to exogenous ghrelin administration. [Copyright &y& Elsevier]

OBJECTIVE: Ghrelin exerts potent GH-releasing activity and stimulates food intake. Circulating ghrelin levels are increased in anorexia and cachexia, reduced in obesity and restored by weight recovery. Newborns are characterized by GH hypersecretion associated with low IGF-I levels reflecting peripheral GH resistance. STUDY DESIGN: The aim of our study was to measure cord ghrelin levels in 117 newborns appropriate for gestational age, born either at term or preterm. RESULTS: Ghrelin levels in cord blood (median; 25th-75th centile: 327.6; 206.0-413.0 pg/ml) were higher ( P < 0.0001) than those in maternal blood at delivery (133.0; 89.0-173.7 pg/ml), without gender differences. A positive correlation between ghrelin levels in mothers and newborns ( r = 0.26, P < 0.01) was observed. Ghrelin levels in newborns born at term (399.0; 229.0-438.0 pg/ml) were remarkably higher ( P < 0.0001) than those in born preterm (208.0; 144.5-278.9 pg/ml). A clear positive association was present between ghrelin levels and gestational age. No association between ghrelin and GH, IGF-I, insulin, glucose and leptin levels were found. CONCLUSIONS: Cord ghrelin levels show clear gestational age-related dependency. The lack of any direct relationship between ghrelin and anthropometric or biochemical parameters in adequate for gestational age newborns does not support the hypothesis that ghrelin has major role in foetal GH secretion and growth. [ABSTRACT FROM AUTHOR]

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 µg/kg); (b) salbutamol infusion (SLB; 0·06 µg/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. [ABSTRACT FROM AUTHOR]