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Growth hormone therapy in children with idiopathic short stature - the effect on appetite and appetite-regulating hormones: a pilot study.
Yackobovitch-Gavan, M, Gat-Yablonski, G, Shtaif, B, Hadani, S, Abargil, S, Phillip, M, Lazar, L
Endocrine research. 2019;(1-2):16-26
Abstract
AIM: To investigate the effect of growth hormone (GH) therapy on appetite-regulating hormones and to examine the association between these hormones and the response to GH, body composition, and resting energy expenditure (REE). METHODS Nine pre-pubertal children with idiopathic short stature underwent a standard meal test before and 4 months following initiation of GH treatment. Ghrelin, GLP-1, leptin, and insulin levels were measured; area under the curve (AUC) was calculated. Height, weight, body composition, REE, and insulin-like growth factor levels were recorded at baseline and after 4 and 12 months. RESULTS Following 4 months of GH therapy, food intake increased, with increased height-standard deviation score (SDS), weight-SDS, and REE (p < .05). Significant changes in appetite-regulating hormones included a decrease in postprandial AUC ghrelin levels (p = .045) and fasting GLP-1 (p = .038), and an increase in fasting insulin (p = .043). Ghrelin levels before GH treatment were positively correlated with the changes in weight-SDS (fasting: r = .667, p = .05; AUC: r = .788, p = .012) and REE (fasting: r = .866, p = .005; AUC: r = .847, p = .008) following 4 months of GH therapy. Ghrelin AUC at 4 months was positively correlated with the changes in height-SDS (r = .741, p = .022) and fat-free-mass (r = .890, p = .001) at 12 months of GH treatment. CONCLUSIONS The reduction in ghrelin and GLP-1 following GH treatment suggests a role for GH in appetite regulation. Fasting and meal-AUC ghrelin levels may serve as biomarkers for predicting short-term (4 months) changes in weight and longer term (12 months) changes in height following GH treatment. The mechanisms linking GH with changes in appetite-regulating hormones remain to be elucidated. ABBREVIATIONS SDS: standard deviation score; REE: resting energy expenditure; SMT: standard meal test; AUC: area under the curve; ISS: idiopathic short stature; SGA: small for gestational age; FFM: fat-free-mass; FM: fat mass; EER: estimated energy requirements; DRI: dietary reference intakes; IQR: inter-quartile range.
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Unacylated ghrelin and obestatin: promising biomarkers of protein energy wasting in children with chronic kidney disease.
Monzani, A, Perrone, M, Prodam, F, Moia, S, Genoni, G, Testa, S, Paglialonga, F, Rapa, A, Bona, G, Montini, G, et al
Pediatric nephrology (Berlin, Germany). 2018;(4):661-672
Abstract
BACKGROUND Impairment in orexigenic/anorexigenic hormone balance may be key in the pathogenesis of protein energy wasting in children with chronic kidney disease (CKD). Measurement of ghrelin and obestatin concentrations in children with CKD would help assess the potential contribution of these hormones to uremic protein energy wasting. METHODS This was a cross-sectional case-control study. Acylated and unacylated ghrelin and obestatin were measured in 42 children on conservative treatment (CT), 20 children on hemodialysis, 48 pediatric renal transplant (RTx) recipients and 43 controls (CTR) (mean age 11.9, range 5-20 years). Weight, height and bicipital, tricipital, subscapular and suprailiac folds were measured, and the body mass index-standard deviation score (BMI-SDS), percentage of fat mass and fat-free mass were calculated. Urea and creatinine were measured and the glomerular filtration rate (GFR) calculated. RESULTS Unacylated ghrelin level was higher in patients than controls (p = 0.0001), with the highest levels found in hemodialysis patients (p = 0.001 vs. CKD-CT, p = 0.0001 vs. RTx, p < 0.0001 vs. CTR). Obestatin level was significantly higher in patients on hemodialysis than those on conservative treatment, RTx recipients and controls (p < 0.0001 in each case). Unacylated ghrelin negatively correlated with weight-SDS (p < 0.0001), BMI-SDS (p = 0.0005) and percentage fat mass (p = 0.004) and positively correlated with percentage fat-free mass (p = 0.004). Obestatin concentration negatively correlated with weight-SDS (p = 0.007). Unacylated ghrelin and obestatin concentrations positively correlated with creatinine and urea and inversely with eGFR, even after adjustments for gender, age, puberty and BMI-SDS (p < 0.0001 for each model). CONCLUSIONS Unacylated ghrelin and obestatin, negatively related to renal function, seem to be promising inverse indicators of nutritional status in children with CKD. Potential therapeutic implications in terms of optimization of their removal in patients on hemodialysis could be hypothesized.
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Interaction of GLP-1 and Ghrelin on Glucose Tolerance in Healthy Humans.
Page, LC, Gastaldelli, A, Gray, SM, D'Alessio, DA, Tong, J
Diabetes. 2018;(10):1976-1985
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Abstract
Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed-nutrient meal. Fifteen healthy men and women completed the study. Each consumed a standard meal on four separate occasions with a superimposed infusion of 1) saline, 2) ghrelin, 3) the GLP-1 receptor antagonist exendin(9-39) (Ex9), or 4) combined ghrelin and Ex9. Similar to previous studies, infusion of ghrelin caused glucose intolerance, whereas Ex9 had a minimal effect. However, combined ghrelin and Ex9 resulted in greater postprandial glycemia than either alone, and this effect was associated with impaired β-cell function and decreased glucose clearance. These findings suggest that in the fed state, stimulation of GLP-1 mitigates some of the effect of ghrelin on glucose tolerance. This novel interaction between gastrointestinal hormones suggests a system that balances insulin secretion and glucose disposal in the fed and fasting states.
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Ghrelin secretion in humans - a role for the vagus nerve?
Veedfald, S, Plamboeck, A, Hartmann, B, Vilsbøll, T, Knop, FK, Deacon, CF, Svendsen, LB, Holst, JJ
Neurogastroenterology and motility. 2018;(6):e13295
Abstract
BACKGROUND Ghrelin, an orexigenic peptide, is secreted from endocrine cells in the gastric mucosa. Circulating levels rise in the preprandial phase, suggesting an anticipatory or cephalic phase of release, and decline in the postprandial phase, suggesting either the loss of a stimulatory factor or inhibition by factors released when nutrients enter the intestine. We hypothesized that vagal signals are not required for the (i) preprandial increase or (ii) postprandial suppression of ghrelin levels. Further, we wanted to investigate the hypothesis that (iii) glucagon-like peptide-1 might be implicated in the postprandial decline in ghrelin levels. METHODS We measured ghrelin levels in plasma from sham-feeding and meal studies carried out in vagotomized individuals and controls, and from a GLP-1 infusion study carried out in fasting healthy young individuals. KEY RESULTS We find that (i) ghrelin secretion is unchanged during indirect vagal stimulation as elicited by modified sham-feeding in vagotomized individuals and matched controls, (ii) ghrelin secretion is similarly suppressed after meal ingestion in vagotomized individuals and controls, and (iii) infusion of GLP-1 does not lower ghrelin levels. CONCLUSIONS & INFERENCES We conclude that for postprandial suppression of circulating ghrelin levels, a circulating factor (but not GLP-1) or short (duodeno-gastric) reflexes seem to be implicated.
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Intragastric infusion of the bitter tastant quinine suppresses hormone release and antral motility during the fasting state in healthy female volunteers.
Deloose, E, Corsetti, M, Van Oudenhove, L, Depoortere, I, Tack, J
Neurogastroenterology and motility. 2018;(1)
Abstract
BACKGROUND Intragastric administration of the bitter tastant denatonium benzoate inhibits the increase of motilin plasma levels and antral contractility. While these findings suggest that gastrointestinal bitter taste receptors could be new targets to modulate gastrointestinal motility and hormone release, they need confirmation with other bitter receptor agonists. The primary aim was to evaluate the effect of intragastric administration of the bitter tastant quinine-hydrochloride (QHCl) on motilin and ghrelin plasma levels. Secondly, we studied the effect on interdigestive motility. METHODS Ten healthy female volunteers were recruited (33±4 y; 22±0.5 kg/m²). Placebo or QHCl (10 μmol/kg) was administered intragastrically through a nasogastric feeding tube after an overnight fast in a single-blind randomized fashion. Administration started 20 min after the first phase III of the migrating motor complex. The measurement continued for another 2 h after the administration. Blood samples were collected every 10 min with the baseline sample taken 10 min prior to administration. KEY RESULTS The increase in plasma levels of motilin (administration; P=.04) and total ghrelin (administration; P=.02) was significantly lower after QHCl. The fluctuation of octanoylated ghrelin was reduced after QHCl (time by administration; P=.03). Duodenal motility did not differ. The fluctuation of antral activity differed over time between placebo and QHCl (time by administration; P=.03). CONCLUSIONS AND INFERENCES QHCl suppresses the increase of both motilin and ghrelin plasma levels. Moreover, QHCl reduced the fluctuation of antral motility. These findings confirm the potential of bitter taste receptors as targets for modifying interdigestive motility in man.
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Acute administration of acyl, but not desacyl ghrelin, decreases blood pressure in healthy humans.
Zhang, CJ, Bidlingmaier, M, Altaye, M, Page, LC, D'Alessio, D, Tschöp, MH, Tong, J
European journal of endocrinology. 2017;(2):123-132
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Abstract
OBJECTIVE To compare the effects of acyl ghrelin (AG) and desacyl ghrelin (DAG) on blood pressure (BP), heart rate (HR) and other autonomic parameters in healthy humans and to elucidate the hormonal mechanisms through which AG could exert its cardiovascular effects. DESIGN Seventeen healthy participants underwent frequent monitoring of systolic (sBP) and diastolic blood pressure (dBP), HR, respiratory rate (RR) and body surface temperature (Temp) during continuous infusion of AG, DAG, combined AG + DAG or saline control before and during an IV glucose tolerance test on 4 separate days. Plasma catecholamines, renin and aldosterone levels were also measured. Differences in outcome measures between treatment groups were assessed using mixed-model analysis. RESULTS Compared to the saline control, AG and combined AG + DAG infusions decreased sBP, dBP, mean arterial blood pressure (MAP), HR and Temp. In contrast, DAG infusion did not alter BP, RR or Temp, but did decrease HR. The AG and AG + DAG infusions also raised plasma aldosterone levels compared to saline (P < 0.001) without affecting renin or catecholamine levels. CONCLUSIONS The decrease in BP, HR, RR and Temp with AG infusion suggests mediation through the autonomic nervous system. The lack of response to DAG suggests that these autonomic effects require activation of the ghrelin receptor.
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Ghrelin is Supressed by Intravenous Alcohol and is Related to Stimulant and Sedative Effects of Alcohol.
Ralevski, E, Horvath, TL, Shanabrough, M, Hayden, R, Newcomb, J, Petrakis, I
Alcohol and alcoholism (Oxford, Oxfordshire). 2017;(4):431-438
Abstract
AIMS: Evidence indicates that feeding-related peptides, such as ghrelin, have a role in the rewarding properties of addictive substances like alcohol. Oral alcohol administration significantly suppresses ghrelin. This study was designed to evaluate the effects of two doses of alcohol on ghrelin and examine if ghrelin levels predict the subjective effects of alcohol. METHODS Healthy social drinkers (N = 20) participated in three, randomly assigned, and counterbalanced laboratory sessions. During each session they received a continuous IV infusion of either placebo (saline), low dose (40 mg%) or high dose (100 mg%) of alcohol. Participants were given a standardized, light breakfast 90 min before the start of the infusion. Ghrelin levels [acyl ghrelin (AG) and total ghrelin (TG)] were collected at four time points before, during and after the infusion. Subjective effects of alcohol, using the BAES, were evaluated before, during and after alcohol infusion. RESULTS IV alcohol significantly reduced AG but not TG levels with no difference between the two doses of alcohol. The percent change (%∆) in AG suppression was substantial in both high dose (43.4%∆), and low dose (39.5%∆) of alcohol. Also, fasting AG and TG levels were significant predictors of alcohol stimulant and sedative effects. Higher fasting ghrelin levels were associated with longer and more intense subjective effects. CONCLUSIONS The results provide evidence that IV alcohol suppresses ghrelin levels similarly to oral alcohol. This study is the first to show that ghrelin predicts subjective effects of alcohol, suggesting that ghrelin may have a role in the rewarding mechanisms for alcohol. SHORT SUMMARY Intravenous alcohol infusion (low dose and high dose of alcohol) when compared to placebo (saline) significantly suppresses ghrelin in healthy social drinkers. Fasting ghrelin levels also predict subjective behavioral effects of alcohol. Those with higher fasting ghrelin levels tend to experience alcohol effects longer and more intensely.
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Improvement of cisplatin-related renal dysfunction by synthetic ghrelin: a prospective randomised phase II trial.
Yanagimoto, Y, Takiguchi, S, Miyazaki, Y, Makino, T, Takahashi, T, Kurokawa, Y, Yamasaki, M, Miyata, H, Nakajima, K, Hosoda, H, et al
British journal of cancer. 2016;(12):1318-25
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BACKGROUND Ghrelin, a 28-amino acid peptide predominantly produced by the stomach, exerts powerful renal protective effects by increasing levels of insulin-like growth factor-1 (IGF-1). The aim of this study was to evaluate the effects of ghrelin on the incidence of renal dysfunction in patients receiving cisplatin-based chemotherapy. METHODS Forty patients with oesophageal cancer receiving cisplatin-based chemotherapy were assigned to either the ghrelin group (n=20), which received ghrelin (0.5 μg kg(-1) h(-1)) for 5 days, or a placebo group (n=20). The primary endpoint was serum creatinine. Secondary endpoints were serum cystatin C, chemotherapy-related adverse events, changes in serum ghrelin-related hormone levels, correlation between markers of renal injury and hormone concentrations, and effects on the second cycle of chemotherapy. RESULTS Blood acyl ghrelin, total ghrelin, and IGF-1 concentrations on day 4 were significantly higher in the ghrelin group. The renal dysfunction, serum creatinine and cystatin C levels, dose reduction, and delay in the initiation of the second cycle of chemotherapy were lower in the ghrelin group than in the control group. Serum creatinine levels were significantly correlated with serum IGF-1 levels. CONCLUSION Continuous synthetic ghrelin administration during cisplatin-based chemotherapy attenuated renal dysfunction and harmful effects on subsequent chemotherapy, possibly by increasing IGF-1 levels.
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Elevation of Fasting Ghrelin in Healthy Human Subjects Consuming a High-Salt Diet: A Novel Mechanism of Obesity?
Zhang, Y, Li, F, Liu, FQ, Chu, C, Wang, Y, Wang, D, Guo, TS, Wang, JK, Guan, GC, Ren, KY, et al
Nutrients. 2016;(6)
Abstract
Overweight/obesity is a chronic disease that carries an increased risk of hypertension, diabetes mellitus, and premature death. Several epidemiological studies have demonstrated a clear relationship between salt intake and obesity, but the pathophysiologic mechanisms remain unknown. We hypothesized that ghrelin, which regulates appetite, food intake, and fat deposition, becomes elevated when one consumes a high-salt diet, contributing to the progression of obesity. We, therefore, investigated fasting ghrelin concentrations during a high-salt diet. Thirty-eight non-obese and normotensive subjects (aged 25 to 50 years) were selected from a rural community in Northern China. They were sequentially maintained on a normal diet for three days at baseline, a low-salt diet for seven days (3 g/day, NaCl), then a high-salt diet for seven days (18 g/day). The concentration of plasma ghrelin was measured using an immunoenzyme method (ELISA). High-salt intake significantly increased fasting ghrelin levels, which were higher during the high-salt diet (320.7 ± 30.6 pg/mL) than during the low-salt diet (172.9 ± 8.9 pg/mL). The comparison of ghrelin levels between the different salt diets was statistically-significantly different (p < 0.01). A positive correlation between 24-h urinary sodium excretion and fasting ghrelin levels was demonstrated. Our data indicate that a high-salt diet elevates fasting ghrelin in healthy human subjects, which may be a novel underlying mechanism of obesity.
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Plasma acyl-ghrelin increases after meal initiation: a new insight.
Seyssel, K, Allirot, X, Nazare, JA, Roth, H, Blond, E, Charrié, A, Mialon, A, Drai, J, Laville, M, Disse, E
European journal of clinical nutrition. 2016;(7):790-4
Abstract
BACKGROUND/OBJECTIVES Plasma ghrelin secretion over time in humans is characterized by pre-prandial increases and by post-prandial decreases all day long. However, some authors who measured ghrelin concentrations around meals showed a rise in plasma ghrelin concentration after meal initiation followed by the typical post-prandial decrease. In order to confirm this observation that has never been discussed, we described ghrelin profiles around four eating episodes in the morning in adult men. SUBJECTS/METHODS Twenty normal-weight and 17 obese men were instructed to eat four fixed meals (706 kJ) 10 min long at 0800 h, 0900 h, 1000 h and 1100 h. Using frequent blood sampling, we determined plasma acyl-ghrelin concentrations around those eating episodes. Glucose, insulin and GLP-1 concentrations were also measured. RESULTS The meals consumption induced a significant increase in plasma acyl-ghrelin concentrations 10 min after meal initiation (P<0.0001): +20.9±5.8 and +10.7±3.3 pg/ml in normal-weight and obese subjects for the first meal; +10.4±3.0 and +5.5±3.9 pg/ml in normal-weight and obese subjects for the second meal; +12.4±3.6 and +4.2±2.1 pg/ml in normal-weight and obese subjects for the third meal; and +4.4±4.1 and +3.3±2.61 pg/ml in normal-weight and obese subjects for the fourth meal. CONCLUSIONS This study is the first to describe and discuss the post-meal initiation ghrelin increase. This finding is consistent in normal-weight and obese individuals.