Short-Term Secretory Regulation of Ghrelin during Growth Hormone Provocative Tests in Prepubertal Children with Various Growth Hormone Secretory Capacities

Abstract

Background and Objective: Ghrelin is a novel gastric peptide which stimulates GH secretion and has been demonstrated to have orexigenic and adipogenic properties. Insulin is a physiological and dynamic modulator of plasma ghrelin, and insulinemia possibly mediates the effect of the nutritional state on the plasma concentrations of ghrelin in adults. No data on the regulation of GH secretion by ghrelin have so far been reported, nor has the possible influence of hypoglycemia on the plasma ghrelin levels in children been reported. Methods: Provocative studies were performed using a variety of stimuli, including insulin-induced hypoglycemia, and glucagon, arginine and L-dopa loading. We studied a group of 27 children with short stature being investigated for GH deficiency (10 F, 17 M; age 4–14 years; height SDS –0.92 to –3.27); the subjects were instructed to fast overnight, and the following morning, the relationships among the plasma ghrelin, GH and glucose levels were investigated by determining the plasma ghrelin profiles during those provocative tests. Using a new method for determining the two types of ghrelin, samples were obtained for determination of the plasma ghrelin, serum glucose and serum GH levels after the administration of the aforementioned stimulating agents. Results: All the four stimuli caused a significant decrease in the circulating C- and N-ghrelin levels with a nadir at +30 min, with the exception of the N-ghrelin level following the L-dopa loading. During the same period, the plasma GH level increased following insulin, arginine and L-dopa loading, and the plasma glucose level increased significantly following glucagon loading. In the arginine and L-dopa load connected, a significant correlation was observed between the 30-min change in the serum GH level and the 30-min change in the plasma C-ghrelin level. In the multiple regression analysis to explain the 30-min change in the plasma level of C-ghrelin, the baseline plasma level of C-ghrelin (basal), height and % overweight were the only three significant parameters, accounting for 85.2% of the variance. Conclusion: This study demonstrated that the inverse relation between the circulating GH and ghrelin levels may indicate the existence of a feedback loop, and also lends support to the assumption of a GH-independent relationship between plasma ghrelin and glucose levels. These observations constitute further evidence to suggest that peripheral ghrelin is a direct growth-promoting hormone.

Ghrelin and growth hormone serum levels during the clonidine test in children with short stature and variable growth hormone status

“…26 The present study demonstrated different ghrelin-GH responses in the two study groups. In accordance with Matsuoka et al, 12 an inverse association was noted between circulating GH and ghrelin levels in the NGH participants, indicating the presence of a negative feedback loop between GH and ghrelin. Moreover, NGH participants exhibited a decline in total ghrelin concentration prior to the GH peak.…”

“…[12][13][14][15] Two studies 12,26 have suggested an inverse relationship between circulating GH and ghrelin levels, indicating the existence of a feedback loop. Hirsh et al failed to relate ghrelin levels to the post-glucagon administration GH release, a finding explained by the authors as a result of the suppressed ghrelin exhibited after glucagon administration.…”

“…Many studies have been conducted in short-stature children in order to assess the presence of a negative feedback loop between GH/IGF-1 axis and ghrelin using different GH provocative tests, with variable results. [12][13][14][15] The variability in the results might be attributed, at least in part, to the fact that ghrelin secretion is closely associated with glucose metabolism, 16 thus the use of insulin or glucagon for GH stimulation may be unsuitable. Clonidine, on the other hand, which has not thus far been used in studies assessing the relationship between ghrelin and GH, could represent a more appropriate stimulus, since it does not affect glucose metabolism.…”

Serum Ghrelin, IGF-I and IGFBP-3 Levels In Children with Normal Variant Short Stature

“…Besides, there is a considerable amount of data in literature that does not support the possible "negative feed-back loop" of GH-IGF-I axis with ghrelin [33,34]. Only Matsuoka et al [35] with their very recent data were able to demonstrate such a negative feed-back loop. Another possible explanation could be that the suboptimal nutritional state in patients with short stature that ends up with lower height SDS could be the reason for the compensatory elevation of ghrelin as an orexigenic factor.…”

The GH-releasing effect of acylated ghrelin in normal subjects is refractory to GH acute auto-feedback but is inhibited after short-term GH administration inducing IGF1 increase

“…Although the physiological role of AG in the control of the somatotropic axis is probably less relevant than originally expected, anyway it remains that the exogenous administration of AG as well as its synthetic analogues such as hexarelin or GHRP6 represents one of the most potent pharmacological stimuli of GH secretion in humans in vivo (20,24,25).…”