Changes of ghrelin following oral glucose tolerance test in obese children with insulin resistance

AIM： To characterize changes in ghrelin levels in response to oral glucose tolerance test （OGTT） and to correlate changes in ghrelin levels with changes in insulin and glucose following OGTT in Chinese obese children of Tanner Ⅰ and Ⅱ stage with insulin resistance. METHODS： 22 obese children with insulin resistance state were divided into four groups according to their Tanner stage and gender： boys of Tanner Ⅰ （fir- Ⅰ ）, boys of Tanner Ⅱ（BT-Ⅱ ）, girls of Tanner Ⅰ （GT- Ⅰ ）, girls of Tanner Ⅱ （GT-Ⅱ）. Ghrelin, insulin and glucose were measured at 0, 30, 60 and 120 rain following OGTT. The control children with normal BMI were divided into control boys of Tanner Ⅰ （CBT- Ⅰ, n = 6）, control boys of Tanner Ⅱ （CBT-Ⅱ, n = 5）, control girls of Tanner Ⅰ （CGT- Ⅰ, n = 6）, control girls of Tanner Ⅱ （CGT-Ⅱ, n = 5）. Fasting serum ghrelin levels were analyzed. RESULTS： Ghrelin levels were lower in obese groups. Ghrelin levels of control group decreased in Tanner Ⅱ stage （CGT- Ⅰ vs CGT-Ⅱ t = -4.703, P = 0.001; CBT- Ⅰ vs CBT- Ⅱ t = -4.794, P = 0.001）. Basal ghrelin levels in fir-Ⅱ decreased more significantly than that in BT- Ⅰ group （t = 2.547, P = 0.029）. Ghrelin levels expressed a downward trend after OGTT among obese children. The decrease in ghrelin levels at 60 min with respect to basal values was 56.9% in BT- Ⅰ. Ghrelin concentrations at 0 min correlated directly with glucose level at 0 min in fir- Ⅰ （r = 0.898, P = 0.015）. There wasn＇t a significant correlation of ghrelin changes with glucose changes and insulin changes during OGTT in obese children with insulin resistance. CONCLUSION： In conclusion, in obese children with insulin resistance, ghrelin levels decreased with advancing pubertal stage. Ghrelin secretion suppression following OGTT was influenced by gender and pubertal stage. Baseline ghrelin levels and ghrelin suppression after OGTT did not significantly correlate with the degree of insulin resistance     

Effects of ghrelin on the insulin and glycemic responses to glucose,arginine, or free fatty acids load in humans

Ghrelin possesses central and peripheral endocrine actions including influence on the endocrine pancreatic function. To clarify this latter ghrelin action, in seven normal young subjects [age (mean +/- SEM), 28.3 +/- 3.1 yr; body mass index, 21.9 +/- 0.9 kg/m(2)), we studied insulin and glucose levels after acute ghrelin administration (1.0 microg/kg i.v.) alone or combined with glucose [oral glucose tolerance test (OGTT), 100 g orally], arginine (ARG, 0.5 g/kg i.v.) or free fatty acid (FFA, Intralipid 10%, 250 ml). Ghrelin inhibited (P < 0.05) insulin and increased (P < 0.05) glucose levels. OGTT increased (P < 0.01) glucose and insulin levels. FFA increased (P < 0.05) glucose but did not modify insulin levels. ARG increased (P < 0.05) both insulin and glucose levels. Ghrelin did not modify both glucose and insulin responses to OGTT as well as the FFA-induced increase in glucose levels; however, ghrelin administration was followed by transient insulin decrease also during FFA. Ghrelin blunted (P < 0.05) the insulin response to ARG and enhanced (P < 0.05) the ARG-induced increase in glucose levels. In all, ghrelin induces transient decrease of spontaneous insulin secretion and selectively blunts the insulin response to ARG but not to oral glucose load. On the other hand, ghrelin raises basal glucose levels and enhances the hyperglycemic effect of ARG but not that of OGTT. These findings support the hypothesis that ghrelin exerts modulatory action of insulin secretion and glucose metabolism in humans.     

Effect of oral glucose administration on ghrelin levels in obese children

OBJECTIVE: Coexpression of GH secretagogue receptor and ghrelin in the pancreas suggests that this peptide is involved in glucose metabolism. Previous reports in adult humans have demonstrated that plasma ghrelin levels decrease after oral glucose administration. However, no data are available in children. Therefore, the aim of this study was to analyze the response of plasma ghrelin levels in obese children after oral glucose administration. SUBJECTS AND METHODS: Twenty-eight obese children ranging from Tanner I to Tanner V were studied. All subjects were given 0.75 g/kg (maximum 75 g) glucose solution after overnight fasting. Ghrelin, insulin, glucose and IGF-binding-protein-1 were determined at 0, 30, 60 and 120 min of the oral glucose tolerance test (OGTT). RESULTS: Basal plasma ghrelin levels were significantly lower than in the respective control groups. These levels decreased significantly during OGTT in obese children, reaching a nadir of 28+/-9% at 60 min in parallel with the maximum increase in glucose levels and previous to maximum insulin levels. CONCLUSION: The rapid fall in plasma ghrelin concentration in obese children after glucose load suggests a mechanism for the control of appetite after food intake.     

Standard light breakfast inhibits circulating ghrelin level to the same extent of oral glucose load in humans, despite different impact on glucose and insulin levels

Ghrelin levels are increased by fasting and energy restriction, decreased by food intake, glucose load and insulin but not by lipids and amino acids. Accordingly, ghrelin levels are elevated in anorexia and cachexia and reduced in obesity. Herein we compared the effects of a standardized light breakfast (SLB) on morning circulating ghrelin levels with those of oral glucose load (OGTT) in normal subjects. Specifically, 8 young adult volunteers [age (mean+/-SEM): 28.0+/-2.0 yr; body mass index (BMI): 22.4+/-0.6 kg/m2] underwent the following testing sessions: a) OGTT (100 g p.o. at 0 min, about 400 kcal); b) SLB (about 400 kcal, 45% carbohydrates, 13% proteins and 42% lipids at 0 min) on three different days; c) placebo (100 ml water p.o.). In all sessions, at baseline, blood samples were withdrawn twice at 5-min interval to characterize the inter- and intra-individual reproducibility of the variables assayed. After placebo and OGTT, blood samples were withdrawn every 15 min up to +120 min. After SLB, blood samples were taken at 60 min only. Ghrelin, insulin and glucose levels were assayed at each time point in all sessions. Similarly to insulin and glucose levels, at baseline, ghrelin showed remarkable intra-subject reproducibility both in the same sessions and among the different sessions. Placebo did not significantly modify ghrelin, insulin and glucose. OGTT increased (p<0.01) glucose (baseline vs peak: 80.0+/-3.6 vs 140.5+/-6.3 mg/dl) and insulin (20.2+/-6.2 vs 115.3+/-10.3 mU/l) levels. SLB increased (p<0.05) both insulin (16.3+/-1.8 vs 48.3+/-6.3 mU/l) and glucose (74.5+/-3.7 vs 82.9+/-3.1 mg/dl) levels. Notably both the insulin and glucose increases after OGTT were significantly higher (p<0.01) than that induced by SLB. After OGTT, ghrelin levels underwent a significant reduction (baseline vs nadir: 355.7+/-150.8 vs 243.3+/-98.8 pg/ml; p<0.05) reaching the nadir at time +60 min. Similarly, ghrelin levels 60 min after SLB (264.8+/-44.8 pg/ml) were significantly (p<0.01) lower than at baseline (341.4+/-54.9 pg/ml). No significant differences in the reduction of ghrelin levels after OGTT and SLB were observed. In conclusion, these findings show that light breakfast inhibits ghrelin secretion to the same extent of OGTT in adults despite lower variations in glucose and insulin levels.     

Circulating ghrelin levels in basal conditions and during glucose tolerance test in acromegalic patients

BACKGROUND: Ghrelin exerts a wide range of metabolic functions. In contrast to the body of information accumulated on the role of ghrelin on energy balance, the possible relevance of the peptide on GH secretion in physiological and pathological conditions has so far been poorly investigated. AIM: The aim of the present study was to evaluate circulating ghrelin levels in acromegalic patients in basal conditions and in response to oral glucose tolerance test (OGTT). PATIENTS: Serum ghrelin, insulin and leptin levels were measured in 31 healthy normal weight subjects as controls, 25 patients with simple obesity and 17 non-diabetic acromegalic patients. Ghrelin and insulin response to OGTT was evaluated in six controls, four obese and six acromegalic patients. RESULTS: The acromegalic patients showed ghrelin levels lower than those observed in normal weight subjects (201+/-20 vs 329+/-32 pmol/l, P<0.05) and similar to those found in obese subjects (165+/-14 pmol/l, P=not significant). Both obese and acromegalic patients had insulin levels significantly higher than controls, while high levels of leptin were detected only in obese subjects. Serum ghrelin levels showed a significant negative correlation with insulin, leptin and body mass index (P<0.05) in normal and obese subjects. No correlation was observed in acromegalic patients, although those with severe insulin resistance showed the lowest ghrelin values (161+/-20 pmol/l). In controls and obese subjects, ghrelin levels showed a significant decrease (25-40%) during OGTT, while no effect was detectable in acromegalic patients. CONCLUSIONS: This study reports that patients with active acromegaly show low levels of circulating ghrelin that are not further reduced by OGTT, this pattern of secretion probably depending on both GH-induced insulin resistance and the putative GH/IGF-I negative feedback control on ghrelin secretion.     

Ghrelin secretion is inhibited by glucose load and insulin-induced hypoglycaemia but unaffected by glucagon and arginine in humans

OBJECTIVE: Circulating ghrelin levels are increased by fasting and decreased by feeding, glucose load, insulin and somatostatin. Whether hyperglycaemia and insulin directly inhibit ghrelin secretion still remains matter of debate. The aim of the present study was therefore to investigate further the regulatory effects of glucose and insulin on ghrelin secretion. DESIGN AND SUBJECTS: We studied the effects of glucose [oral glucose tolerance test (OGTT) 100 g orally], insulin-induced hypoglycaemia [ITT, 0.1 IU/kg insulin intravenously (i.v.)], glucagon (1 mg i.v.), arginine (0.5 mg/kg i.v.) and saline on ghrelin, GH, insulin, glucose and glucagon levels in six normal subjects. MEASUREMENTS: In all the sessions, blood samples were collected every 15 min from 0 up to + 120 min. Ghrelin, GH, insulin, glucagon and glucose levels were assayed at each time point. RESULTS: OGTT increased (P < 0.01) glucose and insulin while decreasing (P < 0.01) GH and ghrelin levels. ITT increased (P < 0.01) GH but decreased (P < 0.01) ghrelin levels. Glucagon increased (P < 0.01) glucose and insulin without modifying GH and ghrelin. Arginine increased (P < 0.01) GH, insulin, glucagon and glucose (P < 0.05) but did not affect ghrelin secretion. CONCLUSIONS: Ghrelin secretion in humans is inhibited by OGTT-induced hyperglycaemia and ITT but not by glucagon and arginine, two substances able to increase insulin and glucose levels. These findings question the assumption that glucose and insulin directly regulate ghrelin secretion. On the other hand, ghrelin secretion is not associated with the GH response to ITT or arginine, indicating that the somatotroph response to these stimuli is unlikely to be mediated by ghrelin.     

Neuroendocrine and metabolic effects of acute ghrelin administration in human obesity

Ghrelin stimulates appetite and plays a role in the neuroendocrine response to energy balance variations. Ghrelin levels are inversely associated with body mass index (BMI), increased by fasting and decreased by food intake, glucose load, insulin, and somatostatin. Ghrelin levels are reduced in obesity, a condition of hyperinsulinism, reduced GH secretion, and hypothalamus-pituitary-adrenal axis hyperactivity. We studied the endocrine and metabolic response to acute ghrelin administration (1.0 microg/kg i.v.) in nine obese women [OB; BMI (mean +/- SD) 36.3 +/- 2.3 kg/m(2)] and seven normal women (NW; BMI 20.3 +/- 1.7 kg/m(2)). Basal ghrelin levels in NW were higher than in OB (P < 0.05). In NW, ghrelin increased (P < 0.05) GH, prolactin (PRL), ACTH, cortisol, and glucose levels but did not modify insulin. In OB, ghrelin increased (P < 0.01) GH, PRL, ACTH, and cortisol levels. The GH response to ghrelin in OB was 55% lower (P < 0.02) than in NW, whereas the PRL, ACTH, and cortisol responses were similar. In OB, ghrelin increased glucose and reduced insulin (P < 0.05). Thus, obesity shows remarkable reduction of the somatotroph responsiveness to ghrelin, suggesting that ghrelin hyposecretion unlikely explains the impairment of somatotroph function in obesity. On the other hand, in obesity ghrelin shows preserved influence on PRL, ACTH, and insulin secretion as well as in glucose levels.     

Ghrelin suppression in overweight children: a manifestation of insulin resistance?

Ghrelin levels increase before and decrease after meals, potentially playing a role in meal initiation and satiety in an inverse pattern to that of insulin. The role of ghrelin in childhood obesity, a state associated with hyperinsulinism and insulin resistance, is not fully understood. Therefore, the aims of the present study were to investigate the dynamics of ghrelin suppression after an oral glucose tolerance test (OGTT) in normal weight (NW) vs overweight (OW) children and the relationship of ghrelin suppression to insulin sensitivity. Thirty-seven NW (15 males and 22 females; 9.4 +/- 0.2 yr old) and 23 OW (13 males and 10 females; 9.4 +/- 0.3 yr old) prepubertal children underwent a 3-h OGTT with measurements of ghrelin, glucose, and insulin. The fasting glucose to insulin ratio and the whole body insulin sensitivity index were used to assess the relationship of insulin sensitivity to fasting ghrelin and ghrelin response to the OGTT, respectively. Fasting ghrelin levels were significantly lower in OW vs NW youth and were mainly influenced by insulin sensitivity independent of adiposity. OGTT-induced absolute suppression in ghrelin was approximately 50% less in OW vs NW children, resulting in a similar percent suppression from baseline in the two groups despite a significantly higher insulin response in OW. The suppression of ghrelin correlated positively with the whole body insulin sensitivity index (r = 0.43; P = 0.001) and negatively with the change in insulin at 30 min (r = -0.31; P = 0.02). Fasting ghrelin, the change in insulin, and the change in glucose during the OGTT were the significant independent variables contributing to the variance in absolute suppression of ghrelin (r2 = 0.42; P < 0.001). Only the change in glucose contributed significantly to the variance in the percent suppression of ghrelin (r2 = 0.14; P = 0.019). Fasting ghrelin and ghrelin suppression after OGTT are modulated by insulin sensitivity. Alterations in ghrelin suppression in OW children may be yet another manifestation of the insulin resistance of obesity. Whether this is responsible for differences in satiety in OW individuals merits additional investigation.     

Plasma ghrelin levels of gastrectomized and vagotomized patients are not affected by glucose administration

BACKGROUND: Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities, secreted mainly by the stomach. Circulating ghrelin concentrations fall rapidly after nutrient ingestion as well as after oral and intravenous glucose challenge. A number of gut hormones including ghrelin require an intact vagal system, which has been hypothesized to have a major role in initiating the postprandial fall in ghrelin levels. AIM: We aimed to investigate the effect of oral glucose challenge on ghrelin secretion in gastrectomized (GASTRX) and vagotomized patients. DESIGN: Interventional study. PATIENTS: Six GASTRX-vagotomized patients and 11 healthy sex- and body mass index (BMI)-matched subjects. METHODS: An oral glucose tolerance test (OGTT) was performed in all subjects. At baseline, circulating plasma total ghrelin, serum glucose, insulin and GH levels were measured. Serum glucose, insulin, GH and plasma ghrelin levels were determined every 30 min for 2 h. RESULTS: Plasma ghrelin levels at baseline were reduced by 55% in GASTRX-vagotomized patients compared to the control group (P < 0.01). In control subjects, plasma ghrelin levels decreased significantly during the OGTT whereas in GASTRX-vagotomized patients no reduction was registered (26.4 +/- 2.8% vs. 5.5 +/- 3.4%). The OGTT revealed a significantly greater increase in circulating glucose levels and serum insulin levels while GH response was not different in GASTRX-vagotomized patients compared to control subjects. CONCLUSIONS: Our data show that circulating ghrelin levels in GASTRX and vagotomized patients were not suppressed after oral glucose administration, unlike control subjects, suggesting that this effect could be due, at least in part, to the lack of contribution of the vagal nervous system to the regulation of ghrelin.     

Ghrelin does not regulate the GH response to insulin-induced hypoglycaemia in children but could be involved in the regulation of cortisol secretion

OBJECTIVE: Ghrelin activates the growth hormone secretagogue receptor GHS-R. It strongly stimulates GH secretion and has a role in energy homeostasis. The relationship between plasma ghrelin and cortisol levels during insulin-induced hypoglycaemia in prepubertal and pubertal children has not yet been investigated. The aim of the present study was to establish whether insulin-induced hypoglycaemia stimulates ghrelin secretion and whether changes in ghrelin concentrations are related to changes in GH and cortisol in children. DESIGN AND PATIENTS: We studied a group of 20 children and adolescents (five girls, 15 boys, mean age 10.8 +/- 3.7 years) undergoing insulin tolerance tests (ITTs) for clinical investigation of GH deficiency. MEASUREMENTS: Stimulation tests were performed to investigate the relationship between ghrelin, GH, cortisol and glucose levels according to age and pubertal stage by determining the ghrelin profiles during insulin-induced hypoglycaemia (at 0, 60 and 120 min). RESULTS: Ghrelin was significantly and inversely related to body weight, height, body mass index (BMI) and age of children (P < 0.05). Significant changes in ghrelin levels (P = 0.00013) were found after the insulin bolus, with a decline at 60 min and an increase to baseline values at 120 min. Changes in cortisol levels were negatively correlated with changes in ghrelin at 60 min (r = -0.59, P = 0.004) and at 120 min (r = -0.605, P = 0.003). CONCLUSIONS: This study shows that ghrelin might not regulate the GH response to insulin-induced hypoglycaemia in prepubertal and pubertal children. A role for ghrelin in the regulation of cortisol secretion can be hypothesized concerning the negative correlation between changes in ghrelin and cortisol. Furthermore, the results imply that ghrelin secretion is age dependent and is a function of growth.     

Acetylcholine regulates ghrelin secretion in humans

Ghrelin secretion has been reportedly increased by fasting and energy restriction but decreased by food intake, glucose, insulin, and somatostatin. However, its regulation is still far from clarified. The cholinergic system mediates some ghrelin actions, e.g. stimulation of gastric contractility and acid secretion and its orexigenic activity. To clarify whether ghrelin secretion undergoes cholinergic control in humans, we studied the effects of pirenzepine [PZ, 100 mg per os (by mouth)], a muscarinic antagonist, or pyridostigmine (PD, 120 mg per os), an indirect cholinergic agonist, on ghrelin, GH, insulin, and glucose levels in six normal subjects. PD increased (P < 0.05) GH (change in area under curves, mean +/- SEM, 790.9 +/- 229.3 microg(*)min/liter) but did not modify insulin and glucose levels. PZ did not significantly modify GH, insulin, and glucose levels. Circulating ghrelin levels were increased by PD (11290.5 +/- 6688.7 pg(*)min/ml; P < 0.05) and reduced by PZ (-23205.0 +/- 8959.5 pg(*)min/ml; P < 0.01). The PD-induced ghrelin peak did not precede that of GH. In conclusion, circulating ghrelin levels in humans are increased and reduced by cholinergic agonists and antagonists, respectively. Thus, ghrelin secretion is under cholinergic, namely muscarinic, control in humans. The variations in circulating ghrelin levels induced by PD and PZ are unlikely to mediate the cholinergic influence on GH secretion.     

Eating pattern and the effect of oral glucose on ghrelin and insulin secretion in patients with anorexia nervosa

OBJECTIVE: Ghrelin is thought to be involved in the regulation of eating behaviour and energy metabolism in acute and chronic feeding states. Circulating plasma ghrelin levels in healthy humans have been found to decrease significantly after oral glucose administration. Because it is suggested that eating behaviour may influence the secretion of ghrelin and insulin in anorexia nervosa (AN), we examined the effect of oral glucose on ghrelin and insulin secretion in subtypes of AN patients. DESIGN AND PATIENTS: Twenty female AN patients and 10 age-matched female controls were subjects. The patients were subdivided into two subtypes based on eating behaviour as follows: 11 restricting type (AN-R), nine binge-eating and purging type (AN-BP). Subjects underwent an oral glucose tolerance test at 08.00 h. Blood was collected 0, 30, 60, 120 and 180 min after the glucose load. RESULTS: Both AN-R and AN-BP had a significant increased basal ghrelin level (P < 0.01) and a significantly decreased basal insulin level (P < 0.05) as compared to controls. The time of the nadir of mean ghrelin in AN-BP (120 min, 58.1% of basal level, 204.9 +/- 34.3 pmol/l, mean +/- SEM) was delayed compared to controls (60 min, 60.2%, 74.3 +/- 7.9 pmol/l), and in the AN-R group it kept decreasing for 180 min (80.0%, 182.4 +/- 31.5 pmol/l). The peaks insulin levels in AN-BP (120 min, 319.3 +/- 88.8 pmol/l) and AN-R (180 min, 418.9 +/- 68.4 pmol/l) were also delayed as compared to controls (60 min, 509.2 +/- 88.8 pmol/l). The glucose level at 180 min in AN-R was significantly (P < 0.05) higher than in controls. CONCLUSIONS: These findings suggest that differences in eating behaviour in AN may induce alterations in both ghrelin and insulin metabolism in the acute feeding state. Furthermore, metabolic changes in the restrictive eating pattern may be related to the pathophysiology of small quantitative meal intake in AN-R patients.     

Acetylcholine does not play a major role in mediating the endocrine responses to ghrelin,a natural ligand of the GH secretagogue receptor,in humans

OBJECTIVE: Ghrelin is a 28 amino residue peptide produced predominantly by the stomach with substantially lower amounts deriving from other central and peripheral tissues. Ghrelin is a natural ligand of the GH secretagogue (GHS) receptor (GHS-R) and possesses a potent GH-releasing activity for which the acylation in serine 3 is essential. Ghrelin also possesses other endocrine and non-endocrine activities reflecting central and peripheral GHS-R distribution and stimulates PRL, ACTH and cortisol secretion, has been reported able to induce hyperglycaemia and to decrease insulin levels and has orexigenic activity. Moreover, ghrelin stimulates gastric motility and acid secretion and its action is mediated by acetylcholine which, in turn, is known to play a stimulatory influence on GH, ACTH and insulin secretion. SUBJECTS AND METHODS: In order to clarify the influence, if any, of acetylcholine on the endocrine activities of ghrelin, we studied the effects of cholinergic enhancement by pyridostigmine (PD, 120 mg p.o. at -60 minutes) and blockade by pirenzepine (PIR, 100 mg p.o. at -60 minutes) on GH, PRL, cortisol, insulin and glucose responses to human acylated ghrelin (1.0 microg/kg i.v. at 0 minutes) in seven normal young volunteers [age (mean +/- SEM): 28.3 +/- 3.1 years; BMI: 21.9 +/- 0.9 kg/m2]. In the same subjects, the effects of PD and PIR on the GH response to GHRH (1.0 microg/kg i.v. at 0 minutes) have also been studied. RESULTS: The administration of ghrelin induced a prompt increase in circulating GH levels (hAUC: 5452.4 +/- 904.9 microg*min/L) which was markedly higher (P < 0.01) than that elicited by GHRH (966.9 +/- 20.50 microg*min/L). Ghrelin also induced a significant increase in PRL (1273.5 +/- 199.7 microg*min/L) and cortisol levels (15505.1 +/- 796.3 microg*min/L) and a decrease in insulin levels (Delta hAUC: -198.1 +/- 39.2 mU*min/L) which was preceded by an increase in plasma glucose levels (8743.8 +/- 593.0 mg*min/dL). The GH response to GHRH was markedly potentiated by PD (4363.3 +/- 917.3 microg*min/L; P < 0.01 vs. GHRH alone). In turn, PD did not modify either the GH response to ghrelin (6564.2 +/- 1753.5 microg*min/L) or its stimulatory effect on PRL and cortisol as well as its effects on insulin and glucose levels. The GH response to GHRH was inhibited by PIR (171.5 +/- 34.7 microg*min/L, P < 0.01 vs. GHRH alone) which, in turn, did not significantly modify the GH response to ghrelin (4044.0 +/- 948.8 microg*min/L). PIR also did not modify the effects of ghrelin on PRL, cortisol, insulin and glucose levels. CONCLUSIONS: The endocrine activities of ghrelin are not affected significantly by cholinergic enhancement and muscarinic blockade. Thus, acetylcholine does not play a major role in the endocrine actions of ghrelin. Moreover, as the cholinergic system influences GH secretion via modulation of somatostatin release, the present data agree with the assumption that ghrelin is partially refractory to the influence of somatostatin.     

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.     

Ghrelin secretion is modulated in a nutrient- and gender-specific manner

BACKGROUND: Ghrelin is a potent GH secretagogue that also plays an important role in appetite and weight regulation. Ghrelin increases hunger and food intake, and its levels decrease after a standard meal or glucose. OBJECTIVE: To examine the effects of standard oral glucose, lipid and protein loads on ghrelin levels, investigating the possibility that these responses may be modulated by several anthropometric and metabolic factors. SUBJECTS AND METHODS: There were 24 adult nondiabetic subjects (13 men/11 women; mean age 55.3 +/- 2.9 years, range 26-74 years). Each participant underwent one or more of the following nutrient loads: (i) a standard oral glucose (75 g) load (n = 18); (ii) an oral lipid load (40 g, with 24 g saturated fat; n = 13); (iii) an oral protein load (40 g; n = 11). RESULTS: Fasting ghrelin levels were negatively related to body mass index (BMI; r =-0.47; P = 0.02), waist circumference (r = -0.58; P = 0.0028), waist/hip ratio (r = -0.56; P = 0.0046), fasting insulin (r = -0.44, P = 0.03), and homeostasis model assessment insulin resistance index (HOMA-R; r = -0.43, P = 0.034). Glucose load induced a decrease in ghrelin levels (P < 0.0001), and this response was modulated by sex (P < 0.0001), in that levels were significantly higher in females. The presence of obesity affected ghrelin response to glucose (< 0.0217), in that log-transformed ghrelin levels started to increase back to baseline after its initial decline earlier in obese than in lean subjects. Ghrelin levels after a glucose load were lower over time in subjects with more pronounced insulin resistance (P < 0.0001). Similarly, ghrelin levels decreased significantly following the lipid meal (P = 0.035), and were modulated by HOMA-R (P = 0.027) and gender (P = 0.029). Protein did not affect ghrelin levels. CONCLUSIONS: This study demonstrates that ghrelin levels respond in a different manner to glucose, lipid and protein loads, and are subject to modulation according to gender, obesity and insulin sensitivity.     

Insulin resistance has no impact on ghrelin suppression in pregnancy

Ghrelin is reduced in various states of insulin resistance. The aim of this study was to examine the relationship between ghrelin and glucose metabolism during pregnancy - a natural insulin-resistant state - in women with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or gestational diabetes mellitus (GDM) and potential changes 3 months after delivery. A total of 54 women, 37 pregnant and with various degrees of insulin resistance and 24 postpartum (PP, seven of them also studied during pregnancy) were studied. Ghrelin plasma concentrations at fasting and 60' following glucose loading (75 g-2 h-oral glucose tolerance test), area under the curve of plasma glucose (G-AUC(OGTT)) and insulin sensitivity [homeostatic model assessment (HOMA) and oral glucose sensitivity index (OGIS) indices, respectively] were determined. Both baseline and 60' ghrelin concentrations were to a comparable degree ( approximately by 65%) suppressed in NGT, IGT and GDM as compared to the PP group (the latter being indistinguishable from NGT regarding glucose tolerance and insulin sensitivity). In all women studied both during and after pregnancy, ghrelin levels rose from pregnancy to PP (mean increase 313.8%; P < 0.03). There was no correlation between baseline ghrelin and insulin sensitivity as estimated from both baseline (HOMA) and dynamic (OGTT:OGIS) glucose and insulin data. Ghrelin is substantially decreased during pregnancy, but glucose-induced ghrelin suppression is preserved at a lower level. There is apparently no relation to the degree of insulin resistance.     

Circulating ghrelin concentrations are lowered by intravenous glucose or hyperinsulinemic euglycemic conditions in rodents

Ghrelin is a peptide secreted mainly by gastric parietal cells that may play a role in appetite regulation. Circulating ghrelin is abruptly lowered by food intake, but factors involved in ghrelin regulation remain unclear. The aim of this study was to determine whether intravenous glucose infusion lowers ghrelin, and to determine whether glucose, insulin or some measure of insulin action best predicts the effect of feeding on ghrelin. Rats were infused over 3 h with either A. saline (controls); B. dextrose to steady state blood glucose approximately 16.7 mM, or C. insulin 7.5 mU/kg x min, plus dextrose as needed to clamp to euglycemic basal concentrations. During 3 h of infusion, group B had significantly greater (P<0.01) glucose, 17.4+/-0.3 mM, than groups A (6.6+/-0.3) or C (6.1+/- 0.2). Groups B and C had hyperinsulinemia at the end of the 3 h infusion (894+/-246, 804+/-156 pM) compared with saline-infused (222+/-24 pM, P<0.01). Ghrelin concentrations were reduced (P<0.01) in both hyperinsulinemic groups (B=85+/-2; C=103+/-0.6 pM) versus controls (163+/-9). Ghrelin was strongly correlated with insulin (r=-0.68), glucose infusion rate (r=-0.75) and free fatty acids (r=0.67), when all 3 groups were combined, although only the 2 latter variables were independent predictors of ghrelin. In conclusion, neither a rise in blood glucose nor presence of nutrient in the stomach is required for the effect of feeding on ghrelin. The data suggest that whole body insulin responsiveness plays either a direct or indirect role in meal-related ghrelin inhibition.     

Dose-dependent inhibition by ghrelin of insulin secretion in the mouse

Ghrelin is produced by stomach oxyntic cells and thought to be involved in the regulation of body weight and food intake. We demonstrate here that the peptide inhibits insulin secretion from overnight-incubated mouse islets in the presence of 8.3, 11.1, and 22.2 mmol/liter glucose. Ghrelin was most efficient at 1 nmol/liter and its effect disappeared by raising the dose more than 25 nmol/liter. Also, insulin secretion in the presence of high K(+) concentrations (20 mmol/liter) was inhibited by ghrelin. Furthermore, when administered iv to mice together with glucose (1 g/kg), ghrelin (50 nmol/kg) inhibited both the rapid 1-min insulin response (364 +/- 90 vs. 985 +/- 114 pmol/liter in controls, P < 0.001) and the area under the 50 min curve of insulin concentration (12.6 +/- 1.2 vs. 15.6 +/- 1.2 nmol/liter x 50 min; P = 0.046) without affecting the glucose disposal rate, insulin sensitivity or glucose effectiveness, i.e. glucose disposal independent from any dynamic change in insulin. The insulinostatic effect of ghrelin was inversely related to insulin sensitivity. In contrast, ghrelin had no influence at the lower dose of 5 nmol/kg and only slightly inhibited insulin secretion at the higher dose of 150 nmol/kg. These findings therefore show that ghrelin inhibits glucose-stimulated insulin secretion in the mouse. The effect is dependent on the dose and elicited on distal signaling steps in islet cells. The results suggest that the islet beta-cells are targets for ghrelin.     

Plasma ghrelin concentrations are decreased in insulin-resistant obese adults relative to equally obese insulin-sensitive controls

Ghrelin, an orexigenic hormone that may play a role in body weight regulation, is reduced in states of obesity. Because obesity is associated with insulin resistance and compensatory hyperinsulinemia, we determined whether these metabolic characteristics were independently associated with suppressed ghrelin concentrations. To investigate this hypothesis, using steady-state plasma glucose concentrations, we identified 20 insulin-resistant (IR) and 20 insulin-sensitive (IS) individuals who were equally obese. The mean body mass indexes were 32.5 +/- 0.4 and 32.0 +/- 0.4 kg/m(2) for the IR and IS groups, respectively. Fasting insulin concentrations were 19.5 and 7.4 micro U/ml (P < 0.001), respectively. Ghrelin concentrations were suppressed in the IR group (252 +/- 19 pg/ml) relative to the IS group (412 +/- 35 pg/ml; P < 0.001). Ghrelin correlated inversely with both insulin resistance (r = -0.64; P < 0.001) and fasting insulin concentration (r = -0.58; P < 0.001). Multivariate analysis confirmed that both insulin resistance and hyperinsulinemia independently predicted low ghrelin concentrations. Our results demonstrate that in obese individuals, insulin resistance and hyperinsulinemia are inversely associated with ghrelin concentrations. Thus, insulin resistance or related metabolic abnormalities may constitute part of a feedback mechanism by which body weight is regulated in humans.     

A variation in the ghrelin gene increases weight and decreases insulin secretion in tall,obese children

Ghrelin is a recently recognized gut-brain peptide originally derived from the gastric mucosa. It stimulates growth hormone release, increases appetite and facilitates fat storage, and may interact with glucose metabolism. We studied the ghrelin gene in a group of 70 tall and obese children (mean age 9.4 year, Z body mass index [BMI] and Z height >3 and/or BMI percentile >99%). We found 10 single nucleotide polymorphisms. One common polymorphism of the ghrelin gene, which corresponds to an amino acid change in the tail of the prepro-ghrelin molecule, was significantly associated with children with a higher BMI (P = 0.001), and with lower insulin secretion during the first part of an oral glucose tolerance test (P = 0.05) although no difference in glucose levels was noted. This might suggest increased insulin sensitivity, although this is not supported by the lack of difference in fasting and 2 hour insulin levels; alternatively, this may be indicative of impaired first phase insulin secretion. These data suggest that variations in the ghrelin gene contribute to obesity in children and may modulate glucose-induced insulin secretion.