Twenty-four hour continuous ghrelin infusion augments physiologically pulsatile, nycthemeral, and entropic (feedback-regulated) modes of growth hormone secretion

Abstract

Background: Ghrelin is a 28-amino acid acylated peptide that potentiates GHRH stimulation and opposes somatostatin inhibition acutely. Whether prolonged ghrelin administration can sustain physiological patterns of GH secretion remains unknown.

Hypothesis: Continuous delivery of ghrelin will amplify physiological patterns of GH secretion over 24 h.

Subjects: Men and women ages 29-69 yr, body mass indices 23-52 kg/m2, were included in the study.

Location: The study was performed at an academic medical center.

Methods: Twenty-four hour continuous sc infusion of saline vs. ghrelin (1 microg/kg.h) with frequent sampling was examined. Deconvolution and entropy analyses were performed.

Outcomes: IGF-I concentrations were determined. Basal, pulsatile, nycthemeral, and entropic measures of GH secretion were calculated.

Results: Ghrelin infusion compared with saline infusion for 24 h elevated (median) acylated ghrelin, GH, and IGF-I concentrations by 8.1-fold (P < 0.001),11-fold (P < 0.001), and 1.4-fold (P = 0.002). GH secretory-burst mass and frequency increased by 6.6-fold (P = 0.004) and 1.7-fold (P < 0.001), respectively, resulting in a 12-fold increase in pulsatile GH secretion (P < 0.001). Interpulse variability decreased significantly (P = 0.046), whereas GH secretory-burst shape and half-life did not change. The amplitude of the nycthemeral GH rhythm increased by 3.4-fold (P < 0.001), and GH patterns became more irregular (higher approximate entropy P < 0.001). Combining GHRH with ghrelin was not an additive in driving GH secretion.

Conclusions: Continuous ghrelin infusion for 24 h elevates acylated ghrelin, GH and IGF-I concentrations, and stimulates pulsatile, nycthemeral, and entropic modes of GH secretion. The consistency of outcomes in a heterogeneous cohort of adults suggests potentially broad utility of this physiological secretagogue in hyposomatotropic states.

Figure 1

Dose-related stimulation of 24-h pulsatile and basal GH secretion (top) and incremental IGF-I concentrations (bottom) across a 30-fold range of ghrelin infusion rates in a total of 15 volunteers. The results of linear (top) and curvilinear logistical (bottom) regression analyses are given. The GH response to 3.0 μg/kg·h ghrelin departs markedly (P < 0.001) from the strongly linear initial response, suggesting feedback inhibition, response down-regulation, or an asymptotic maximum (rate limiting step) in the GH response.

Figure 2

Mean (± sem) plasma GH concentration profiles over 24 h for all four interventions (Subjects and Methods). N, Cohort size; MN, midnight.

Figure 3

Stimulatory effects of ghrelin and combined ghrelin/GHRH on IGF-I concentrations. IGF-I was measured in serum collected at 0900 h just before and again at 0900 h at the end of each 24-h infusion. Comparisons are by paired Student’s t tests. Data are the mean ± sem. N, Number of subjects.

Figure 4

Mean (top) and maximal (bottom) GH concentrations in adults administered ghrelin (1 μg/kg·h) or GHRH (1 μg/kg·h) or both compared with saline (placebo) for 24 h. Data are the mean ± sem. P values were determined by ANOVA. Columns with different (unshared) alphabetic superscripts differ significantly by Tukey’s post hoc test. N, Number of subjects.

Figure 5

A, Augmentation of 24-h pulsatile GH secretion by administration of ghrelin (1 μg/kg·h) and combined ghrelin/GHRH (both 1 μg/kg·h) over placebo and GHRH (1 μg/kg·h). B, Predominant (77%) increase in GH secretory-burst mass (top) with lesser (23%) increase in detectable burst frequency (bottom) induced by ghrelin and ghrelin/GHRH infusions. See Fig. 4 format. NS, P > 0.05.

Figure 6

Twenty-four hour GH rhythmicity defined by the amplitude (top), phase (time of zenith, middle), and cosine mean (bottom) in the four interventions. Data are presented as described in Fig. 4.

Figure 7

Effects of ghrelin, GHRH, and both peptides on the relative randomness (irregularity, ApEn) of the GH secretory process over 24 h. Higher ApEn denotes less feedback inhibition. The format is given in Fig. 4.