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The acute ghrelin response to a psychological stress challenge does not predict the post-stress urge to eat.
Rouach, V, Bloch, M, Rosenberg, N, Gilad, S, Limor, R, Stern, N, Greenman, Y
Psychoneuroendocrinology. 2007;(6):693-702
Abstract
Ghrelin is a growth hormone and cortisol secretagogue that plays an important role in appetite and weight regulation. It is not known whether ghrelin is involved in the eating response to stress in humans. In the present study we examined the effects of psychologically induced stress on plasma ghrelin levels in patients with binge-eating disorder (BED) (n=8) and in healthy subjects of normal (n=8) or increased (n=8) body mass index (BMI). Volunteers were subjected to the standardized trier social stress test (TSST). Heart rate, blood pressure, serum cortisol, serum prolactin, and plasma ghrelin levels were measured throughout the test. In addition, subjects were requested to rate their feelings of anxiety, tension, urge to eat uncontrollably and desire to eat sweets by means of a visual analog scale both before and after the TSST. There was a significant rise in the systolic blood pressure (p=0.003) in the study population, reflecting induction of physiological changes by the psychological challenge. Basal ghrelin levels were higher in healthy normal weight (385.4+/-79 pg/ml) than in obese (170.4+/-15.7 pg/ml) subjects (p<0.033). Basal ghrelin levels in patients with BED (240+/-40.8 pg/ml) were at an intermediate level between thin and healthy obese subjects, but this difference did not attain statistical significance. There were no differences in ghrelin levels throughout the test among the groups after correction for BMI, age and gender. A significant difference in the trend time of ghrelin was revealed when the three groups were analyzed according to their cortisol response to stress. Ghrelin levels increased in cortisol responders whereas no change or a decrease in ghrelin levels occurred in cortisol non-responders (p=0.038). Furthermore, a positive correlation was found between the change in ghrelin and the change in cortisol during TSST (r=0.444, p=0.029) but not between the change in ghrelin and the change in systolic blood pressure. The combined score of stress and anxiety was higher in subjects in the higher quartile of ghrelin response in comparison to the lower quartile both before (28.3+/-6.5 vs. 6.6+/-3.3, p=0.0077) and after (61.6+/-9 vs. 28.3+/-11.3, p=0.033) TSST. On the other hand, eating related scores did not differ according to quartiles of ghrelin response. Our findings indicate that a psychological stress may induce an increase in plasma ghrelin levels in humans, and that the post-stress induced urge for uncontrolled eating is not acutely modulated by stress related elevations in ghrelin levels. Furthermore, the stress induced increase in plasma ghrelin was associated with the acute response of serum cortisol to stress, but was independent of BMI or the presence of BED.
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Fasting ghrelin does not predict food intake after short-term energy restriction.
Blom, WA, Mars, M, Hendriks, HF, de Groot, LC, Stafleu, A, Kok, FJ, de Graaf, C
Obesity (Silver Spring, Md.). 2006;(5):838-46
Abstract
OBJECTIVE To study the role of ghrelin as a hunger signal during energy restriction and to test the hypothesis that changes in fasting leptin concentrations during energy restriction are associated with changes in fasting ghrelin concentrations. RESEARCH METHODS AND PROCEDURES Thirty-five healthy, lean men (23 +/- 3 years of age; BMI: 22.3 +/- 1.6 kg/m(2)) participated in a controlled intervention study. Fasting ghrelin and leptin concentrations were measured before and after 2 days of 62% energy restriction and after a 2-day period of ad libitum food intake. Energy intake during the latter period was assessed. RESULTS On average, ghrelin concentrations did not change (0.05 mug/liter; 95% confidence interval, -0.03; 0.12) during energy restriction. Changes in ghrelin concentration during energy restriction were not associated with energy intake during the ad libitum period (r = 0.07; not significant). Ad libitum energy intake was, however, associated with the change in ghrelin concentrations during the same period (r = -0.34; p = 0.05). Ghrelin and leptin concentrations were not associated. In addition, the ratio of percentage changes in ghrelin and leptin during energy restriction was not correlated with ad libitum food intake after energy restriction (r = -0.26; p = 0.14). DISCUSSION Fasting ghrelin concentrations did not rise after a 2-day energy restriction regimen. Moreover, changes in ghrelin concentrations during energy restriction were not associated with subsequent ad libitum food intake, suggesting that fasting ghrelin does not act as a hunger signal to the brain. The data did not support our hypothesis that leptin suppresses ghrelin levels.
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Circulating ghrelin is decreased in non-obese and obese women with binge eating disorder as well as in obese non-binge eating women, but not in patients with bulimia nervosa.
Monteleone, P, Fabrazzo, M, Tortorella, A, Martiadis, V, Serritella, C, Maj, M
Psychoneuroendocrinology. 2005;(3):243-50
Abstract
Ghrelin is a peripheral gastric peptide involved in the regulation of eating behavior and energy homeostasis. While changes in ghrelin plasma levels have been found in anorexia nervosa, bulimia nervosa (BN) and obesity, no study has assessed circulating ghrelin in binge eating disorder (BED). Therefore, we measured plasma levels of this peptide in women with BED as compared to women with BN, obesity and healthy controls. One hundred and eighty-two drug-free women (56 bulimics, 13 non-obese and 34 obese BED subjects, 28 obese non-binge eating women and 51 non-obese healthy women) underwent psychopathological and nutritional assessments and blood sample collection for glucose and ghrelin assays in the morning. As compared to non-obese healthy women, both non-obese and obese BED women as well as obese non-binge eating women had significantly increased values of body weight, body mass index and body fat mass. Moreover, plasma ghrelin concentrations were significantly decreased in both non-obese (P<0.01) and obese (P<0.0001) BED women as well as in obese non-binge eating women (P<0.001) but not in women with BN. No significant correlations emerged between plasma ghrelin values and the frequency of binge/vomiting in BN subjects or the frequency of bingeing in BED individuals. The reduction of plasma ghrelin in non-obese and obese binge eaters as well as in obese non-binge eaters may represent a secondary change aiming to counteract their positive energy imbalance.
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Prandial regulation of ghrelin secretion in humans: does glucagon contribute to the preprandial increase in circulating ghrelin?
Soule, S, Pemberton, C, Hunt, P, Cole, D, Raudsepp, S, Inder, W
Clinical endocrinology. 2005;(4):412-7
Abstract
OBJECTIVE Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects. SUBJECTS AND MEASUREMENTS Nine healthy volunteers, mean age 47 years (range 33-58) and body mass index (BMI) 24 kg/m2 (range 20.9-27.6) were recruited and received either 1 mg glucagon (n = 9) or 1 ml saline (n = 6) subcutaneously on separate days between 0800 and 0830 h after an overnight fast. Venous blood was then sampled at 15-min intervals during the first hour, followed by 30-min intervals up to 4 h for glucose, insulin, GH, cortisol, somatostatin and ghrelin. RESULTS Mean +/- SE basal ghrelin was 213.1 +/- 34.3 pmol/l and decreased significantly by 15 min after glucagon administration to 179.3 +/- 28 pmol/l (P = 0.01), then remaining suppressed relative to the basal value until 240 min after glucagon. Plasma insulin increased from a basal value of 46.7 +/- 7.7 pmol/l to a peak of 327.1 +/- 54.9 pmol/l (P < 0.0001). There was an inverse statistical relationship between the increase in insulin over the first 120 min and the decrease in ghrelin (P = 0.005), while somatostatin, GH and glucose were not significant contributors to the decrease in ghrelin (P > 0.05). Mean +/- SE basal GH was 7.3 +/- 2.9 microg/l and increased by 150 min after glucagon to a peak of 20.5 +/- 6.8 microg/l (P = 0.006). Changes in neither ghrelin nor glucose were related to the increase in GH (P = 0.7). Saline administration did not produce any significant change in ghrelin, insulin or somatostatin although the expected diurnal reduction in cortisol (P < 0.05) was observed. CONCLUSIONS Our study found no evidence that glucagon stimulates ghrelin secretion in humans and supports the hypothesis that insulin is a negative regulator of ghrelin secretion in the postprandial state. We did not find a negative relationship between endogenous somatostatin and ghrelin despite earlier reports that exogenously administered somatostatin analogues suppress plasma ghrelin. Finally, glucagon-induced GH secretion is not mediated by an increase in plasma ghrelin.
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Acute plasma ghrelin and leptin responses to oral feeding or intraperitoneal hypertonic glucose-based dialysate in patients with chronic renal failure.
Pérez-Fontán, M, Cordido, F, Rodríguez-Carmona, A, García-Naveiro, R, Isidro, ML, Villaverde, P, García-Buela, J
Kidney international. 2005;(6):2877-85
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Abstract
BACKGROUND Chronic renal failure (CRF) is associated with increased plasma levels of ghrelin and leptin, but the regulation of the secretion of these hormones has been insufficiently studied, in this setting. The aim of this study was to analyze the acute effects of oral feeding or intraperitoneal 3.86% glucose-based dialysate infusion on plasma ghrelin and leptin levels in patients with CRF undergoing peritoneal dialysis (PD). METHODS Following a crossover design, 10 patients and eight healthy controls underwent a standardized oral intake, a 3.86% glucose-based dialysate PD exchange (patients) and placebo oral intake. We scrutinized acute changes in plasma ghrelin, leptin, glucose, insulin, and growth hormone (GH) levels. RESULTS In patients, total ghrelin decreased modestly immediately after oral feeding (nadir 90.6% of baseline, range 85.1, 94.5, P= 0.03) or the PD exchange test (92.2%, range 58.7, 101.9, P= 0.05) (median). Response to oral feeding was markedly blunted when compared with healthy individuals (73.8%, range 56.1, 89.1, P= 0.007) (P < 0.005 vs. patients). Plasma acyl-ghrelin had a less marked but more persistent decay after the PD exchange test (nadir 80.4%, range 55.1, 96.3, P= 0.02) than after oral intake (64.4%, range 45.6, 82.3, P= 0.005); again, changes were more intense in normal controls (47.4%, range 32.1, 67.3, P= 0.01) (P < 0.05 vs. patients). Leptin levels decreased slightly (P < 0.05) after the PD exchange in patients, but did not respond acutely to oral feeding in patients or controls. CONCLUSION Ghrelin secretion is partially refractory to the acute inhibitory effect of oral feeding in patients with CRF undergoing PD therapy. A 3.86% glucose-based PD exchange results in a significant decrease of plasma ghrelin levels. Plasma leptin levels are not acutely affected by oral feeding in patients with CRF or healthy individuals.
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[Lowered ghrelin levels in acromegaly—normalization after treatment].
Kozakowski, J, Rabijewski, M, Zgliczyński, W
Endokrynologia Polska. 2005;(6):862-70
Abstract
UNLABELLED Ghrelin has been found as a natural ligand of growth hormone secretagouges receptors (GHSR-1a) that exerts a marked stimulatory effect on growth hormone (GH) secretion. It is also thought to be involved of eating behavior and control of energy homeostasis. However, still little is known about the physiology of ghrelin secretion in acromegaly. OBJECTIVE The objective of the study was to examine effects of surgical and pharmacological treatment in patients with acromegaly on serum ghrelin levels. MATERIAL 28 patients (17 women and 11 men) aged 47.7+/-11.4 years (mean+/-SD) with body mass index (BMI)=31.6+/-4.9 kg/m2. Diagnosis was based on: 1/peak GH in oral glucose tolerance test>or=1ng/mL, 2/serum IGF-1 levels above normal for gender and age, 3/ pituitary adenoma in magnetic resonance imagining. Patients were divided into two groups: Group I-surgically treated (transsphenoidal surgery): 10 women and 7 men aged 45+/-10.9 years with BMI=31.3+/-4.9 kg/m2. Criteria of cure in acromaegaly were: 1/peak GH<1 ng/ml in OGTT, 2/serum IGHF-1 levels according to gender and age. Group II-pharmacologically treated (Sandostatin LAR, Novartis Pharm. Ltd, 20 mg im, monthly): 7 women and 4 men aged 52+/-11 years, BMI=29.4 kg/m2. Criteria of good control of acromegaly were: 1/peak GH<1 ng/ml in OGTT, 2/serum IGHF-1 levels according to gender and age. Control group-healthy subjects: 10 women and 19 men aged 47.7+/-11.4 years, BMI=25.6 kg/m2. METHODS In patients before and after treatment and in healthy subjects fasting serum levels of total ghrelin, leptin, growth hormone (GH), insulin-like growth factor I (IGF-1), glucose, insulin, total cholesterol and trigliceryde levels were measured. HOMA index of insulin resistance was calculated. The patients and control subjects underwent assessment of body height, weight and BMI. RESULTS Body weight and BMI in patients before treatment were higher compared to healthy controls (87.3+/-18 to 74.4+/-16 kg, p<0.02 (body weight) and 31.6+/-4.9 to 25.5+/-4.1 kg/m2, p<0.0002 (BMI). Body weight and BMI after successful surgical treatment were still higher compared to healthy subjects (92.7+/-19 to 74.4+/-16 kg, p=0.02 (body weight) and 31.5+/-5 to 25.5+/-4.1 kg/m2, p<0.0003 (BMI). Body weight decreased during pharmacological treatment although BMI was still higher then in control subjects (30.1+/-6.3 to 25.2+/-4.1 kg/m2; p<0.003). Serum fasting GH and IGF-1 levels decreased after successful surgical treatment, from 26.3+/-29 to 1.6+/-2.5 microg/l (p<0.007) and from 926.1+/-325 to 337+/-213 microg/l (p<0.00003), respectively. Also during pharmacological treatment decrease in serum GH and IGF-1 levels were observed, from 29.4+/-40 to 5.8+/-7.6 microg/l and from 976.3+/-328 to 358.3+/-203 microg/l (p<0.002), respectively. Serum insulin levels decreased after successful surgical treatment, from 29.1+/-9.8 do 15.8+/-7.3 microU/ml (p<0.02). Also during pharmacological treatment serum insulin levels and HOMA index decreased, from 29.8+/-12.9 to 14.6+/-2.1 microU/ml (p<0.03) and from 9.1+/-3.6 to 3.5+/-0.4 (p<0.007), respectively. Serum fasting insulin and glucose levels and HOMA index were higher in patients before treatment compared to healthy subjects and didn't differ significantly after successful surgery and during pharmacotherapy. Serum ghrelin levels in patients with acromegaly were decreased compared to healthy subjects (1055.2+/-325 to 1266.8+/-374 pg/ml, p<0.04) and increased after successful surgical treatment, from 1164.2+/-321 to 1553.6+/-542 pg/ml (p=0.01). During pharmacotherapy decrease in serum ghrelin levels was observed, from 1038.7+/-344 to 568.5 +/-252 pg/ml (p<0.03). There were no significant differences in serum ghrelin level between healthy controls and patients after treatment. Significant negative correlation between serum ghrelin levels and body weight (r=-0.40, p=0.04) in healthy subjects was found. In patients with acromegaly significant negative correlation between serum ghrelin levels and insulin levels and HOMA index were found (r=-0.48; p<0.02 and r=-0.57; p<0.03, respectively. CONCLUSIONS In patients with acromegaly: 1/serum ghrelin levels are decreased compared to healthy subjects. It can be speculated, that its at least partially caused by negative feedback control of ghrelin production and by GH-induced hyperinsulinaemia. 2/serum ghrelin levels increase after successful transsphenoidal surgery. 3/ treatment with somatostatin analoges causes decrease in serum ghrelin levels, despite of serum GH and IGF-1 normalization.
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Postprandial ghrelin release in anorectic patients before and after weight gain.
Otto, B, Tschöp, M, Frühauf, E, Heldwein, W, Fichter, M, Otto, C, Cuntz, U
Psychoneuroendocrinology. 2005;(6):577-81
Abstract
The appetite-modulating hormone ghrelin transmits changes in food intake to the central nervous system. In patients with anorexia nervosa, weight gain reduces elevated fasting ghrelin levels to normal, however, less is known about the effects on postprandial ghrelin levels. In 20 female anorectic in-patients (25.6 +/- 1.0 years; body mass index (BMI) 15.1 +/- 0.3 kg/m2) a standardized test with 250 ml fluid meal (250 kcal: 9.4 g protein, 34.4 g carbohydrates, and 8.3 g fat) was performed at three different times (at admission, after partial weight gain of at least 2 kg, and at discharge) and compared to healthy controls (n = 6; BMI 21.1 +/- 0.7 kg/m2). Plasma ghrelin levels were measured preprandially as well as 20 and 60 min postprandially by a commercially available radioimmunoassay (Phoenix Pharmaceuticals, USA). At admission plasma ghrelin levels significantly decreased postprandially (from 871.9 +/- 124 to 620.3 +/- 80 pg/ml 60 min after meal; P < 0.005). After partial weight gain (2.8 +/- 0.1 kg; BMI 16.1 +/- 0.3 kg/m2) postprandial ghrelin concentrations decreased from 597.0 +/- 79 to 414.7 +/- 39 pg/ml (P < 0.0001), at discharge (weight gain: 7.6 +/- 0.5 kg; BMI 17.9 +/- 0.4 kg/m2) from 570.4 +/- 78 to 395.4 +/- 44 pg/ml (P < 0.0001). Mean postprandial ghrelin decrease was not significantly different between the three tests (29, 25, and 26%, respectively) or to controls (20%). In anorectic patients mean postprandial ghrelin decrease did not change during weight gain. These findings indicate that in anorexia nervosa the suppression of ghrelin release by acute changes of energy balance (feeding) is not disturbed and that it is independent from chronic changes in energy balance (weight gain).
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Correlation of serum ghrelin levels with body mass index and carbohydrate metabolism in patients treated with atypical antipsychotics.
Palik, E, Birkás, KD, Faludi, G, Karádi, I, Cseh, K
Diabetes research and clinical practice. 2005;:S60-4
Abstract
The prevalence of diabetes mellitus and metabolic syndrome is higher in patients with schizophrenia than in the normal population. Atypical antipsychotic drugs are used in psychiatry since the beginning of 1990. These drugs differ from the "typical" antipsychotics used previously, as they have less extrapyramidal side effects, and because of this they are tolerated better, but are associated with weight-gain and disturbances in carbohydrate metabolism. Ghrelin is an orexigen hormone partaking in body weight regulation. It is produced in the enteroendocrine P/D1 cells of the gastric mucosa and secreted to the circulation. The aim of our study was to determine ghrelin levels of atypical antipsychotic-treated patients in relationship with their body mass index (BMI) and carbohydrate metabolism. We measured the fasting serum ghrelin levels in 56 patients (male/female: 16/40, age mean+/-S.D.: 50.6+/-5.6 years) treated with atypical antipsychotics (clozapine, olanzapine, risperidon and quetiapine), and in 75 healthy control subjects, age and gender matched (RIA Linco, USA) in relationship with their BMI and their fasting and 75 g OGTT 120 min blood glucose values. The serum ghrelin levels of the patient group were notably higher (1333+/-659 pg/ml) than in the control group (368+/-103, p<0.0001; Mann-Whitney). We found no difference among the four antipsychotics in weight-gain, diabetes prevalence and the serum ghrelin levels. The BMI of the patient group was significantly higher (29.3+/-7.2 kg/m2 versus 24.3+/-3.7 kg/m2, p<0.0001; Mann-Whitney); 32% of them had blood glucose abnormality (18/56). There was no difference between the ghrelin levels in diabetic and non-diabetic patients. We found a significant negative linear correlation between the serum ghrelin and BMI (r=-0.35, p=0.0078; Spearman), the ghrelin and fasting blood glucose (r=-0.32, p=0.015) and OGTT 75 g 120 min blood glucose levels (r=-0.27, p=0.036). The orexigen effect of elevated serum ghrelin levels can contribute to the weight-gain and high diabetes prevalence associated with atypical antipsychotic treatment. The link between atypical antipsychotic treatment and elevated serum ghrelin levels is unknown so far, but a dysregulation of the central feedback mechanism can be hypothesised.
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Hyperthyroidism is associated with suppressed circulating ghrelin levels.
Riis, AL, Hansen, TK, Møller, N, Weeke, J, Jørgensen, JO
The Journal of clinical endocrinology and metabolism. 2003;(2):853-7
Abstract
Ghrelin stimulates GH secretion as well as appetite and food intake. To explore whether ghrelin is involved in the regulation of appetite and body weight in hyperthyroidism, circulating ghrelin levels were measured in nine hyperthyroid patients before and after medical treatment and compared with those in eight healthy control subjects. All participants were studied in the postabsorptive state and during a 3-h euglycemic hyperinsulinemic clamp. Before treatment the patients had 3- to 5-fold elevations of T(3), and during treatment the patients gained 5 kg of body weight. Ghrelin levels were decreased in hyperthyroidism both in the fasting state (hyperthyroid, 1080 +/- 195 pg/ml; euthyroid, 1480 +/- 215 pg/ml; P = 0.03) and during clamp (hyperthyroid, 833 +/- 150 pg/ml; euthyroid, 1210 +/- 180 pg/m; P = 0.02). After treatment, ghrelin levels did not differ from those in control subjects. In all three study groups the clamp significantly reduced ghrelin levels compared with fasting levels. In conclusion, ghrelin levels are reduced in hyperthyroidism and become normalized by medical antithyroid treatment. Hyperinsulinemia suppresses ghrelin regardless of thyroid status. Ghrelin is not a primary stimulator of appetite and food intake in hyperthyroidism, and the mechanisms underlying the suppressive effect of hyperthyroidism on ghrelin secretion remain unclear.
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Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients.
Edén Engström, B, Burman, P, Holdstock, C, Karlsson, FA
The Journal of clinical endocrinology and metabolism. 2003;(11):5193-8
Abstract
Ghrelin is a recently discovered gastric peptide that increases appetite, glucose oxidation, and lipogenesis and stimulates the secretion of GH. In contrast to ghrelin, GH promotes lipolysis, glucose production, and insulin secretion. Both ghrelin and GH are suppressed by intake of nutrients, especially glucose. The role of GH in the regulation of ghrelin has not yet been established. We investigated the effect of GH on circulating levels of ghrelin in relation to its effects on glucose, insulin, body composition, and the adipocyte-derived peptides leptin and adiponectin. Thirty-six patients with adult-onset GH deficiency received recombinant human GH for 9 months in a placebo-controlled study. Body composition and fasting serum analytes were assessed at baseline and at the end of the study. The GH treatment was accompanied by increased serum levels of IGF-I, reduced body weight (-2%) and body fat (-27%), and increased serum concentrations of glucose (+10%) and insulin (+48%). Ghrelin levels decreased in 30 of 36 subjects by a mean of -29%, and leptin decreased by a mean of -24%. Adiponectin increased in the women only. The decreases in ghrelin and leptin correlated with changes in fat mass, fat-free mass, and IGF-I. The reductions in ghrelin were predicted independently of the changes in IGF-I and fat mass. It is likely that the reductions in ghrelin and leptin reflect the metabolic effects of GH on lipid mobilization and glucose production. Possibly, a suppression of ghrelin promotes loss of body fat in GH-deficient patients receiving treatment. The observed correlation between the changes in ghrelin and IGF-I may suggest that the GH/IGF-I axis has a negative feedback on ghrelin secretion.