Serum ghrelin levels are inversely correlated with body mass index,age, and insulin concentrations in normal children and are markedly increased in Prader-Willi syndrome

Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.     

Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: changes during development

Background Prader–Willi syndrome (PWS) is associated with failure to thrive in infancy and progressive hyperphagia and obesity in childhood. This progressive weight gain is associated with hyperghrelinaemia and increased insulin sensitivity. The role of ghrelin excess in the pathogenesis of obesity is unclear. Objective To determine if high ghrelin levels precede the onset of obesity in young PWS children. Design and methods A cross‐sectional study of 33 infants with PWS and 28 healthy control subjects (C). Fasting ghrelin and other satiety hormones were measured. Results Median total serum ghrelin in young children with PWS trended higher, but did not differ significantly from those in C of similar age, weight‐for‐age z‐score and sex. However, there was more variability in ghrelin concentrations of young PWS. Eleven of 33 PWS subjects had ghrelin levels greater than the 95th percentile for ghrelin values in the C subjects (> 2871 pg/ml). Six of the PWS subjects with high ghrelin levels had weight‐for‐age z‐scores < 0. Ghrelin concentrations in PWS and C infants exceeded those in older children. In youngsters with PWS, leptin was higher, suggesting a relative excess of fat to lean body mass and plasma adiponectin was increased. Conclusions Young infants with PWS who have not yet developed hyperphagia or obesity have median fasting ghrelin levels similar to controls. However, a subset (33%) of young PWS is hyperghrelinaemic; approximately one‐half of those with hyperghrelinaemia have BMI z‐score < 0. The age‐related decline in ghrelin is blunted in PWS.     

High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder occurring in 1 of 10,000-16,000 live births and is characterized by excessive appetite with progressive massive obesity as well as short stature and mental retardation. Most patients have GH deficiency and hypogonadotropic hypogonadism. The causes of the hyperphagia and abnormal GH secretion are unknown. To determine whether ghrelin, a novel GH secretagogue with orexigenic properties, is elevated in PWS, we measured fasting plasma ghrelin concentration; body composition (dual-energy x-ray absorptiometry); and subjective ratings of hunger (visual analog scale) in seven subjects (6 males and 1 female; age, 26 +/- 7 yr; body fat, 39 +/- 11%, mean +/- SD) with PWS (diagnosis confirmed by genetic test) and 30 healthy subjects (reference population, 15 males and 15 females; age, 32 +/- 7 yr; body fat, 36 +/- 11%) fasted overnight. All subjects were weight stable for at least 6 months before admission to the study. The mean plasma ghrelin concentration was higher in PWS than in the reference population (307 +/- 164 vs. 109 +/- 24 fmol/ml; P < 0.001), and this difference remained significant after adjustment for percentage body fat (P < 0.001). Plasma ghrelin was also higher (P = 0.0004) in PWS than in five healthy subjects fasted for 36 h. A positive correlation was found between plasma ghrelin and subjective ratings of hunger (r = 0.71; P = 0.008). Furthermore, in subjects with PWS, the concentration of the hormone was not different before and after ingestion of 2 ml and a satiating amount of the same liquid meal (ghrelin concentrations: 307 +/- 164 vs. 306 +/- 205 vs. 260 +/- 134 fmol/ml, respectively; ANOVA for repeated measures, P = 0.56). This is the first evidence that ghrelin, a novel orexigenic hormone, is elevated in subjects with PWS. Our finding suggests that ghrelin may be responsible, at least in part, for the hyperphagia observed in PWS.     

Hyperghrelinemia does not accelerate gastric emptying in Prader-Willi syndrome patients

Prader-Willi syndrome (PWS) is the most common form of syndromic obesity associated with hyperphagia. Because ghrelin stimulates gastric motility in rodents, and PWS patients have 3- to 4-fold higher fasting plasma ghrelin concentrations than normal subjects, we hypothesized that hyperphagia associated with PWS may be partly explained by rapid gastric emptying due to the increased gastric motility caused by ghrelin. We determined gastric emptying times (GETs) and measured ghrelin levels in 11 PWS children and 11 age-, sex-, and body mass index-matched controls using a standard meal containing [(99m)Tc]diaminetriaminepentacetate. Median plasma ghrelin levels before (precibum) and after the GET study were higher in PWS patients than in controls (P = 0.004 and P = 0.001, respectively). Median percent gastric retentions at 90 min after the standard meal were 57.1% (range, 34.0-83.2%) in PWS patients and 40.2% (range, 27.2-60.2%) in controls (P = 0.03). In particular, precibum ghrelin concentrations were not significantly correlated with the rate of gastric emptying in PWS patients (P = 0.153; r = 0.461) or controls (P = 0.911; r = 0.048). Our results show that gastric emptying in PWS is reduced despite higher ghrelin levels, and that the voracious appetite associated with PWS is related to another mechanism.     

Peptides associated with hyperphagia in adults with Prader–Willi syndrome before and during GH treatment

Prader-Willi syndrome (PWS) is a complex genetic disorder characterised by mild mental retardation and distinct physical, behavioural, and psychiatric features. One of the cardinal symptoms is excessive eating, which--if left untreated--leads to extreme obesity. In the present study we have examined circulating levels of peptides with documented association to hyperphagia in young adults with PWS. Since growth hormone (GH) is often used nowadays to correct GH insufficiency during childhood PWS, we also studied the impact of GH administration on the peptides. Seventeen adults, 9 men and 8 women, 17-32 years of age with a mean BMI of 35+/-3.2 kg/m(2) participated. All had clinical PWS (Holm's criteria). Genetic testing was performed in all patients and in 11 the diagnosis was confirmed. They were randomized to treatment with either placebo or GH (Genotropin, Pharmacia Corporation) for 6 months. Subsequently all received open label treatment to provide all subjects with 12 months active GH treatment. Doses were individually titrated. Weight, BMI, oxytocin (baseline only), leptin, Neuropeptide Y (NPY), and ghrelin were evaluated at baseline and after 6 and 12 months. At baseline plasma mean oxytocin was within and serum ghrelin just above the normal range (14.7+/-1.2 pmol/L and 0.87+/-0.12 microg/L, respectively). Serum leptin levels were high above and plasma NPY levels within the lower normal range (47.8+/-29.1 microg/L and 13+/-1 pmol/L, respectively). Results were independent of genotype. No changes in mean BMI, ghrelin, leptin or NPY were seen following GH treatment.CONCLUSION: Leptin levels were in general high reflecting obesity and as a consequence NPY levels were low. In simple obesity oxytocin levels are high, while ghrelin levels are suppressed. In view of the adiposity oxytocin circulated in abnormally low and ghrelin in abnormally high concentrations in our patients. GH treatment of PWS patients did not change ghrelin, leptin or NPY. We suggest that both oxytocin and ghrelin are involved in the pathogenesis of hyperphagia seen in PWS.     

The effect of growth hormone on the response of total and acylated ghrelin to a standardized oral glucose load and insulin resistance in children with Prader-Willi syndrome

CONTEXT: Fasting levels of plasma ghrelins are grossly elevated in children with Prader-Willi syndrome (PWS). The cause of this elevation and the regulation of ghrelins in PWS is largely unknown. The regulatory role of individual nutritional components and of GH is not well characterized. OBJECTIVE: We investigated the influence of GH on acylated (aGhr) and total ghrelin (tGhr) concentrations before and after an oral glucose load, and on insulin resistance in PWS children. DESIGN, PATIENTS, AND INTERVENTIONS: In a clinical follow-up study, plasma ghrelins were measured during an oral glucose tolerance test, and parameters of insulin resistance were determined in 28 PWS children before and/or 1.18 (0.42-9.6) yr (median, range) after start of GH therapy (0.035 mg/kg body weight per day). MAIN OUTCOME MEASURES: Fasting and postglucose concentrations of aGhr and tGhr and homeostasis model assessment 2 insulin resistance were the main outcome measures. SETTING: The study was conducted in a single center (University Children's Hospital). Results: High fasting [1060 +/- 292 (sd) pg/ml; n = 12] and postglucose trough (801 +/- 303 pg/ml; n = 10) tGhr concentrations in GH-untreated PWS children were found to be decreased in the GH-treated group (fasting 761 +/- 247 pg/ml, n = 24, P = 0.006; postglucose 500 +/- 176 pg/ml, n = 20; P = 0.006). In contrast, aGhr concentrations and insulin resistance were not changed by GH treatment. Both aGhr and tGhr concentrations were decreased by oral carbohydrate administration, independent of the GH treatment status. CONCLUSIONS: Our results indicate that, in PWS children, aGhr and tGhr are differentially regulated by GH.     

Adiponectin levels in prepubertal children with Prader-Willi syndrome before and during growth hormone therapy

CONTEXT: Children with Prader-Willi syndrome (PWS) may have obesity and an abnormal body composition with a high body fat percentage, even if they have a normal body weight. Adiponectin has been inversely related to obesity and insulin resistance. OBJECTIVE: The objective of the study was to evaluate in prepubertal PWS children the following: 1) adiponectin levels, body composition, carbohydrate metabolism, and triglyceride levels; 2) associations between adiponectin and body composition, carbohydrate metabolism, and triglycerides; and 3) effects of GH treatment on these outcome measures. PATIENTS: Twenty prepubertal PWS children participated in the study. INTERVENTION: The subjects were randomized into a GH treatment group (n=10, 1 mg/m2.d) and a non-GH-treated control group (n=10). MAIN OUTCOME MEASURES: At baseline, after 1 and 2 yr of GH treatment, fasting levels of adiponectin, glucose, insulin, and triglycerides were assessed. Body composition and fat distribution were measured by dual energy x-ray absorptiometry. RESULTS: PWS children had significantly higher median (interquartile range) adiponectin levels [17.1 mg/liter (13.9-23.2)] than healthy sex- and age-matched controls [11.8 mg/liter (9.7-12.5), P<0.005]. Body fat percentage was significantly higher than 0 sd score [1.8 sd score (1.5-2.1), P<0.001]. Adiponectin levels were inversely related to triglyceride levels (r=-0.52, P=0.03). There was a tendency to an inverse relation with body fat percentage and body mass index, but no correlation with fasting insulin or glucose levels, the insulin to glucose ratio, or homeostasis model assessment index. During GH treatment, adiponectin levels increased significantly and did not change in randomized controls. CONCLUSION: Adiponectin levels were increased, and inversely associated with triglyceride levels, in prepubertal, not overweight PWS children, although they had a relatively high body fat percentage. During GH treatment, adiponectin levels further increased, whereas no change was found in the controls, which is reassuring with respect to the development of insulin resistance during GH treatment.     

Somatostatin infusion lowers plasma ghrelin without reducing appetite in adults with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is characterized by life-threatening childhood-onset hyperphagia, obesity and, uniquely, high plasma levels of ghrelin, the orexigenic gastric hormone. Somatostatin suppresses ghrelin secretion in normal subjects. We therefore examined the effect of somatostatin on plasma ghrelin and appetite in four male PWS adults fasted overnight in a double-blind, placebo-controlled, randomized cross-over study. Subjects received an intravenous infusion of somatostatin (250 microg/hr) or saline for 300 min, and had blood samples taken every 30 min for measurement of plasma ghrelin and PYY3-36 (anorexigenic intestinal hormone) by radio-immunoassay, and glucose. Appetite was measured by counting sandwiches eaten over a 60 min free food access period from +120 min. Despite somatostatin lowering fasting plasma ghrelin by 60 +/- 2% (P = 0.04) to levels seen in non-PWS men, there was no associated reduction in food intake (105 +/- 9% of food intake during saline infusion, P = 0.6). Somatostatin also lowered plasma PYY levels by 45 +/- 16% (P = 0.04), and produced post-prandial hyperglycemia (P = 0.04). We conclude that either hyperghrelinemia may not contribute to hyperphagia in PWS adults, or perhaps concomitant reductions in anorexigenic gastrointestinal hormones by somatostatin counteracted any anorexigenic effect of lowering orexigenic ghrelin. Somatostatin analogues may therefore not be an effective therapy for obesity in PWS. Larger chronic studies with long-acting somatostatin analogues will be needed to determine their benefits and risks in treating PWS obesity.     

Weight loss increases circulating levels of ghrelin in human obesity

OBJECTIVE: Ghrelin, a novel endogenous ligand for the GH secretagogue receptor, has been reported to have adipogenic actions and induce weight gain in addition to its GH-releasing properties. Interestingly, recent data indicate that ghrelin is downregulated in human obesity, which is also known to be accompanied by reduced GH levels. PATIENTS AND METHODS: To investigate the influence of weight loss on circulating levels of ghrelin we recruited eight obese women among patients attending a 6-month weight-loss course organized by The Danish Heart Association. We measured body composition including computerized tomography as well as fasting plasma ghrelin concentrations before and after weight loss. RESULTS: Plasma ghrelin concentrations increased by 12% following weight loss (P < 0.01), and the increase in ghrelin levels was positively correlated with the extent of weight loss (r = 0.68, P < 0.05). Exposure to exogenous GH intravenously did not influence fasting ghrelin levels either before or after weight loss. Our data further suggest the existence of hyperghrelinaemia in a single subject with long-standing obesity but no signs of GH excess. CONCLUSIONS: This study provides evidence of a reversible suppression of ghrelin associated with obesity. The feasibility of measuring ghrelin in the circulation provides a new tool for the investigation of the complex hormonal regulation of appetite and energy balance.     

Effects of growth hormone on pulmonary function,sleep quality,behavior, cognition,growth velocity,body composition,and resting energy expenditure in Prader-Willi syndrome

The objective of this study was to investigate the effects of GH administration on pulmonary function, sleep, behavior, cognition, linear growth velocity, body composition, and resting energy expenditure (REE) in children with Prader-Willi syndrome. The study used a 12-month, balanced, randomized, double-blind, placebo-controlled, cross-over experimental design. Twelve subjects were randomized to GH (0.043 mg/kg x d) or placebo intervention for 6 months and then crossed over to the alternate intervention for 6 months. Differences in outcome variables were determined by paired t tests. Peak flow rate, percentage vital capacity, and forced expiratory flow rate improved and number of hypopnea and apnea events and duration of apnea events trended toward improvement after GH intervention. The only difference in cognition or behavior was an increase in hyperactivity scale on the Behavior Assessment System for Children after GH intervention. Linear growth velocity, REE, and lean mass were higher (67%, 19%, and 7.6%, respectively), and fat mass and percentage body fat were lower (10.3% and 8.1%, respectively) after GH intervention. GH administration did not change mean fasting ghrelin concentration. GH intervention improved body composition and REE and may contribute to better sleep quality and pulmonary function. GH administration did not impact fasting ghrelin concentration.     

Correlation between fasting plasma ghrelin levels and age, body mass index (BMI), BMI percentiles, and 24-hour plasma ghrelin profiles in Prader-Willi syndrome

Ghrelin is a GH-releasing acylated peptide found in the stomach and a centrally acting food intake stimulator. Prader-Willi syndrome (PWS) is a genetic disorder characterized by a voracious appetite and increased fasting ghrelin levels. In this report we describe 24-h ghrelin profiles in PWS children (n = 5) and compare these with age, sex, and body mass index (BMI)-matched controls (n = 5). A 3- to 4-fold increase in ghrelin levels was found in PWS over a 24-h period, compared with controls (P < 0.001). Interestingly, there was a greater tendency for the up-regulation of ghrelin level in lean PWS than in obese PWS. To confirm this finding, we measured fasting ghrelin levels in 39 patients with PWS. Inverse correlations were found between plasma ghrelin levels and the following: age (r = -0.408, P = 0.005), BMI (r = -0.341, P = 0.017), percentage of the ideal weight for age (r = -0.382, P = 0.008), and BMI percentile (r = -0.311, P = 0.027). Our data show that there may be a suppressive (or up-regulating) controlling mechanism of ghrelin secretion in obese (or lean) PWS children. We hope that our data may further explain the mechanisms underlying the insatiable appetite and obesity characteristic of PWS.     

Ghrelin immunoreactivity in human plasma is suppressed by somatostatin

OBJECTIVE: Ghrelin was recently identified as a specific endogenous ligand for the growth hormone secretagogue receptor (GHS-R). This new hormone was isolated from rat and human stomach and was reported to circulate in human plasma, but the regulation and physiological significance of ghrelin in humans have not been clarified. The present study was undertaken to test the following hypotheses: (1) prolonged fasting, which is known to stimulate GH secretion, is associated with changes in ghrelin immunoreactivity; (2) somatostatin in the systemic circulation regulates ghrelin secretion; and (3) GH affects ghrelin levels. DESIGN AND PATIENTS: The study population included normal subjects investigated on three occasions (fasting alone, fasting and somatostatin infusion +/- GH); GH-deficient adults investigated after 12 and 36 h of fasting +/- GH, as well as patients with active acromegaly before and after somatostatin analogue treatment. RESULTS: Somatostatin infusion lowered ghrelin levels 70-80% (P < 0.0001), whereas continued fasting +/- GH did not significantly affect ghrelin levels. In active acromegaly, suppression of plasma ghrelin levels was recorded after a single subcutaneous octreotide injection as well as during prolonged administration of slow-release octreotide. CONCLUSIONS: (1) Amplification of GH release during prolonged fasting is not caused by an increase in ghrelin immunoreactivity, (2) systemic somatostatin suppresses plasma ghrelin levels independently of GH status, and (3) the feasibility of measuring ghrelin in the circulation provides an opportunity for studying the interaction between hormones and nutrition.     

Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy

The orexigenic peptide, ghrelin, is regulated by acute and chronic nutritional state. Although exogenously administered ghrelin stimulates pituitary GH secretion, little is known about the role of ghrelin in endogenous GH secretion or how high GH and IGF-I levels in acromegaly could affect ghrelin secretion and vice versa. Therefore, we evaluated fasting and post oral glucose tolerance test serum ghrelin levels in 19 patients with active acromegaly at baseline and after either surgery in 9 of these or administration of long-acting octreotide (Sandostatin LAR) in the other 10 patients. After surgical cure, fasting ghrelin rose from 312 +/- 56 pg/ml to 548 +/- 97 pg/ml (P = 0.013). Fasting serum ghrelin levels were higher in all patients after surgery and ranged between 112% and 349% of presurgery levels. Ghrelin levels fell significantly during long-acting octreotide therapy from 447 +/- 34 pg/ml to 206 +/- 15 pg/ml (P < 0.0001); ghrelin levels on octreotide ranged between 26% and 70% of baseline levels. Serum ghrelin levels were suppressed significantly during the oral glucose tolerance test in both groups. Pretherapy ghrelin levels correlated negatively with serum insulin levels (r = -0.494; P = 0.03) and insulin resistance as estimated by the homeostasis model assessment score (r = -0.573; P = 0.01). In patients without diabetes mellitus, serum insulin levels in the surgical group were 19.7 +/- 5.4 microU/ml before surgery and fell to 9.7 +/- 0.93 microU/ml after surgery (P = 0.05); levels in the octreotide group were 13.9 +/- 2.8 microU/ml before and fell to 11.2 +/- 2.8 microU/ml on octreotide (P = 0.03). Pretherapy ghrelin levels did not correlate with weight or body mass index, but after therapy in the surgery group ghrelin correlated negatively with weight (r = -0.823, P = 0.012) as has been demonstrated by others in healthy subjects. Ghrelin secretion is dysregulated in active acromegaly; lowered serum levels of ghrelin in active acromegaly rise along with the postsurgery normalization of GH and IGF-I and improved insulin resistance. In contrast to surgical therapy, long-acting octreotide therapy persistently suppressed serum ghrelin levels. It remains to be determined whether altered circulating ghrelin concentrations could impact on body composition changes in acromegaly.     

Fasting and postprandial total ghrelin remain unchanged after short-term energy restriction

Adaptations that promote positive energy balance appear in response to dietary restriction. The aim of this study was to determine whether fasting and postprandial total ghrelin increase in response to short-term energy restriction. Fifteen adult male subjects were subjected to a 4-d energy restricted diet (-800 kcal/d). Body weight and composition, resting energy expenditure, respiratory quotient, fasting and postprandial appetite scores, and fasting and postprandial serum leptin and total ghrelin were determined before and after dietary intervention. Despite the fact that fat mass remained unchanged after the 4 d, fasting (-36%; P 相似文献   

Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study

Obesity, poor growth, and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a GH-deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. While short-term benefits of treatment with GH have been shown, whether these beneficial effects are dose dependent and persist or wane with prolonged therapy remains uncertain. Effects of 24 additional months of GH treatment at varying doses (0.3, 1.0, and 1.5 mg/m(2).d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 46 children with PWS, who had previously been treated with GH therapy (1 mg/m(2).d) for 12-24 months. Percent body fat, lean muscle mass, and bone mineral density (BMD) were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotient. A modified Bruininks-Oseretski test of physical performance evaluated strength and agility. During months 24-48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and REE occurred with GH therapy doses of 1.0 and 1.5 mg/m(2).d (P < 0.05), but not with 0.3 mg/m(2).d. BMD continued to improve at all doses of GH (P < 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. Salutary and sustained GH-induced changes in growth, body composition, BMD, and physical function in children with PWS can be achieved with daily administration of GH doses > or =1 mg/m(2). Lower doses of GH, (0.3 mg/m(2).d) effective in improving body composition in GHD adults, do not appear to be effective in children with PWS at sustaining improvement in body composition.     

Endocrine and metabolic aspects of adult Prader-Willi syndrome with special emphasis on the effect of growth hormone treatment.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by mild mental retardation, short stature, abnormal body composition, muscular hypotonia and distinctive behavioural features. Excessive eating causes progressive obesity with increased cardiovascular morbidity and mortality. In the PWS genotype loss of one or more normally active paternal genes in region q11-13 on chromosome 15 is seen. It is supposed that the genetic alteration leads to dysfunction of several hypothalamic centres and growth hormone (GH) deficiency (GHD) is common. PWS is well described in children, in whom GH treatment improves body composition, linear growth, physical strength and agility. Few studies have focused on adults. We examined a cohort of 19 young adults with clinical PWS (13 with positive genotype) and mean BMI of 35 kg/m2. At baseline the activity of the GH-insulin-like growth factor-I (IGF-I) system was impaired with low GH values, low total IGF-I and in relation to the obesity low levels of free IGF-I and non-suppressed IGF-binding-protein-1 (IGFBP-1). 2/3 were hypogonadal. Bone mineral density (BMD) was low. Four patients had impaired glucose tolerance and nine patients high homeostasis model assessment (HOMA) index, indicating insulin resistance. Seven patients had a moderate dyslipidemia. The 13 patients with the PWS genotype were shorter and had significantly lower IGF-I. Seventeen (9 men and 8 women), subsequently completed a 12 months GH treatment trial, and GH had beneficial effects on body composition without significant adverse effects. The effects were more pronounced in the patients with the PWS genotype. Analysis of peptides involved in appetite regulation showed that leptin levels were high reflecting obesity and as a consequence NPY levels were low. In relation to the patients obesity circulating oxytocin levels were abnormally low and ghrelin levels abnormally high. Thus, oxytocin and ghrelin might be involved in the hyperphagia. NPY, leptin and ghrelin did not change during GH treatment.In conclusion this pilot study showed that adults with PWS have a partial GH deficiency, and GH treatment has beneficial effects on body composition in adult PWS without significant side-effects. Larger and longer term studies on the effect of GH replacement in adult PWS are encouraged.     

Elevated fasting plasma ghrelin in prader-willi syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance

Plasma ghrelin is elevated in Prader-Willi syndrome (PWS). This might contribute to obesity or GH deficiency in such patients. Visceral adiposity and insulin resistance are reduced in PWS, which might lead to hyperghrelinemia. We measured fasting plasma ghrelin in control female (n = 39), PWS female (n = 12), and PWS male (n = 6) adults. In controls and PWS, ghrelin was negatively correlated with visceral adiposity, fasting insulin, and homeostasis model insulin resistance index. There was no significant correlation with serum IGF-I in PWS. In stepwise linear regression, visceral adiposity (P < 0.02) had a stronger inverse correlation with ghrelin than sc fat depots in controls and PWS, possibly through hyperinsulinemia, as the correlations with insulin resistance were even stronger (P < 0.01). PWS females had significantly (P < 0.001) elevated ghrelin (mean +/- SD, 661 +/- 360 pg/ml), compared with both nonobese (363 +/- 163) and obese (191 +/- 66) controls. Ghrelin was increased 3.4- to 3.6-fold in PWS females adjusting for total adiposity, 3.2- to 3.4-fold adjusting for visceral adiposity, and 3.0-fold adjusting for insulin resistance. Fasting plasma glucagon-like peptide-1 was normal in PWS females. The hyperghrelinemia in PWS adults is therefore not solely explained by their reduced visceral adiposity and relative hypoinsulinemia. Its cause and consequences await further elucidation.     

Cross-sectional and prospective relationships of fasting plasma ghrelin concentrations with anthropometric measures in pima Indian children

Ghrelin, a recently discovered GH secretagogue with orexigenic effects, is proposed to be a regulator of energy balance. To test whether fasting plasma ghrelin concentrations predict future gain in body weight or adiposity, we measured weight, height, body mass index (BMI), percentage of body fat (by dual energy x-ray absorptiometry), and fasting plasma concentrations of ghrelin, insulin, and glucose in 10-yr-old Pima Indians (n = 40; 13 males and 27 females) and subsequent weight, height, and BMI 1.7 +/- 0.6 yr later. At baseline, the fasting plasma ghrelin concentration was negatively associated with height (r = -0.52; P = 0.0006), weight, (r = -0.37; P = 0.02), percentage of body fat (r = -0.33, P = 0.04), and fasting plasma insulin concentration (r = -0.41; P = 0.01). In multiple regression models adjusting for gender and fasting plasma insulin, the fasting plasma ghrelin concentration was an independent determinant of height (beta = -13.9; P = 0.02), but not weight or BMI. Prospectively, the baseline fasting plasma ghrelin concentration was not an independent determinant of the relative rate of increase in weight, height, or adiposity. In conclusion, the fasting plasma ghrelin concentration was lower in taller and fatter Pima Indian children, but did not independently predict baseline weight, adiposity, or future growth rates. These data do not support a direct relationship between the fasting plasma ghrelin concentration and subsequent relative changes in height or weight in growing children.     

Fasting and postprandial hyperghrelinemia in Prader-Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma

The cause of the unique elevation in fasting plasma levels of the orexigenic gastric hormone ghrelin in many patients with Prader-Willi syndrome (PWS) is unclear. We measured fasting and postprandial plasma ghrelin in nonobese (n = 16 fasting and n = 8 postprandial) and obese non-PWS adults (n = 16 and 9), adults with genetically confirmed PWS (n = 26 and 10), and patients with hypothalamic obesity from craniopharyngioma tumors (n = 9 and 6). We show that 1) plasma ghrelin levels decline normally after food consumption in PWS, but there is still fasting and postprandial hyperghrelinemia relative to the patient's obesity (2.0-fold higher fasting ghrelin, 1.8-fold higher postprandial ghrelin, adjusting for percentage of body fat); 2) the fasting and postprandial hyperghrelinemia in PWS appears to be at least partially, but possibly not solely, explained by the concurrent relative hypoinsulinemia and preserved insulin sensitivity for the patient's obesity (residual 1.3- to 1.6-fold higher fasting ghrelin, 1.2- to 1.5-fold higher postprandial ghrelin in PWS, adjusting for insulin levels or homeostasis model assessment of insulin resistance); 3) hyperghrelinemia and hypoinsulinemia are not found in craniopharyngioma patients with hypothalamic obesity, and indeed, these patients have relative hyperinsulinemia for their obesity; and 4) there is no deficiency of the anorexigenic intestinal hormone peptide YY(3-36) in PWS contributing to their hyperghrelinemia.     

Increased density of ghrelin-expressing cells in the gastric fundus and body in Prader-Willi syndrome

CONTEXT: The levels of ghrelin, an orexigenic hormone secreted by oxyntic cells in the digestive tract, are elevated in Prader-Willi syndrome (PWS) and GH deficiency (GHD) patients. In this study, we hypothesized that the hyperghrelinemia observed in PWS is related to IGF-I or GH/IGF axis deficiency. DESIGN: We investigated the densities of ghrelin-expressing cells (GECs), the amounts of ghrelin in gastric tissues, and ghrelin levels in plasma in 16 PWS patients and compared these results with those of 13 GHD patients and comparison groups (19 normal lean and 10 normal obese subjects). RESULTS: In the gastric body and fundus, 2- to 3-fold increases in the numbers of GECs (P < 0.001) and in the amounts of ghrelin (P < 0.018) were noted in PWS patients vs. comparison groups, whereas GEC numbers in GHD patients were similar to those of the comparison group despite elevated fasting plasma ghrelin levels. In addition, IGF-I sd scores in PWS were not found to be correlated with GEC densities, the amounts of ghrelin expressed in gastric tissues, or plasma ghrelin levels. CONCLUSIONS: Our results suggest that IGF-I or GH/IGF axis deficiency appears to be unrelated to observed GEC increases in the stomach of patients with PWS.