Meals inhibited secretion of both ghrelin and des-acyl ghrelin, yet long-term fasting inhibited acylation but not total secretion. Acylation may be regulated independently of secretion by nutrient availability in the gut or by esterases that cleave the acyl group. These studies highlight the importance of stringent conditions for sample collection and evaluation of full-length ghrelin and des-acyl ghrelin using specific two-site assays.
The acute GH release stimulated by the synthetic hexapeptide, His-DTrp-Ala-Trp-DPhe-Lys-NH2 [GH releasing peptide (GHRP)], was determined in 18 normal men and compared with the effects of GH-releasing hormone, GHRH-(1-44)-NH2. Specificity of effect was assessed by measurement of serum PRL, LH, TSH, and cortisol. GHRP was administered at doses of 0.1, 0.3, and 1.0 microgram/kg by iv bolus. GHRH at a dose of 1.0 microgram/kg was administered alone and together with various does of GHRP. No adverse clinical effects of laboratory abnormalities were observed in response to GHRP. A side-effect of mild facial flushing of 1- to 3-min duration occurred in 16 of the 18 subjects who received GHRH-(1-44)-NH2. Mean (+/- SEM) peak serum GH levels after injection of placebo and 0.1, 0.3, and 1.0 microgram/kg GHRP were 1.2 +/- 0.3, 7.6 +/- 2.5, 16.5 +/- 4.1, and 68.7 +/- 15.5 micrograms/L, respectively. The submaximal dosages of 0.1 and 0.3 microgram/kg GHRP plus 1 microgram/kg GHRH stimulated GH release synergistically. Serum PRL and cortisol levels rose about 2-fold above basal levels only at the 1 microgram/kg dose of GHRP, and there were no changes in serum LH and TSH over the first hour after administration of the peptide(s). GHRP is a potent secretagogue of GH in normal men. Since GHRP and GHRH together stimulate GH release synergistically, these results suggest that GHRP and GHRH act independently. This supports our hypothesis that the GH-releasing activity of GHRP reflects a new physiological system in need of further characterization in animals and man.
Background Growth hormone (GH) secretion and muscle mass decline from mid-puberty throughout life culminating in sarcopenia, frailty, decreased function and loss of independence. Objective Determine if an oral ghrelin mimetic (MK-677) would enhance GH secretion into the young adult range without serious adverse effects, prevent the decline of fat-free mass (FFM), and decrease abdominal visceral fat (AVF) in healthy older adults. Design Two-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial. Setting General Clinical Research Center study performed at a University Hospital. Participants Sixty-five healthy men and women (on or off hormone replacement therapy) ages 60-81. Intervention Oral administration of MK-677 (25 mg) or placebo once daily. Measurements Growth hormone and insulin-like growth factor-I (IGF-I); FFM and AVF were the primary endpoints after one year of treatment. Other endpoints: weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function and quality of life; all endpoints were assessed at baseline and every 6 months. Limitations Study design (duration and subject number) not sufficient to evaluate functional endpoints in healthy elderly Results Daily MK-677 significantly increased GH and IGF-I levels to those of healthy young adults without serious adverse effects. With placebo, mean (95% Cl) FFM decreased -0.5 (-1.1 to 0.2) kg, however, FFM increased 1.1 (0.7 to 1.5) kg with MK-677 (P<0.001, MK-677 vs. placebo); body cell mass as reflected by intracellular water decreased -1.0 (-2.1 to 0.2) kg with placebo, but increased 0.8 (-0.1 to 1.6) kg with MK-677 (P=0.021). There were no significant differences in AVF or total fat mass. However, the average increase in limb fat in the MK-677 group (1.1 kg) was greater than with placebo (0.24 kg); P=0.001. Body weight increased 0.8 (-0.3 to 1.8) kg with placebo and 2.7 (2.0 to 3.5) kg with MK-677 (P=0.003). Fasting blood glucose increased an average of 0.3 mmol/L (5 mg/dL) with MK-677 (P=0.015) and insulin sensitivity declined. The most frequent side effects were an increase in appetite that subsided within a few months and transient, mild lower extremity edema and muscle pain. Low density lipoprotein cholesterol decreased -0.14 (-0.27 to -0.01) mmol/L [-5.4 (-10.4 to -0.4) mg/dL] with MK-677 (P=0.026); there were no differences in total or high density lipoprotein cholesterol. Cortisol increased 47 (28 to 71) nmol/L [1.7 (1.0 to 2.6 µg/dL)] with MK-677 (P=0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677-treated subjects. Increased FFM did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results. Conclusions The ghrelin mimetic MK-677 enhanced pulsatile GH secretion and significantly increased FFM over 12 months and was generally well tolerated. Long-term functional, and ultimately pharmaco-economic, studies in elderly adults...
Our data support the hypothesis that under normal conditions in subjects given regular meals endogenous acyl-ghrelin acts to increase the amplitude of GH pulses.
Aging is associated with declining activity of the GH axis, possibly contributing to adverse body composition changes and increased incidence of cardiovascular disease. The stimulatory effects on the GH-insulin-like growth factor I (IGF-I) axis of orally administered MK-677, a GH-releasing peptide mimetic, were investigated. Thirty-two healthy subjects (15 women and 17 men, aged 64-81 yr) were enrolled in a randomized, double blind, placebo-controlled trial. They received placebo or 2, 10, or 25 mg MK-677, orally, once daily for 2 separate study periods of 14 and 28 days. At baseline and on day 14 of each study period, blood was collected every 20 min for 24 h to measure GH, PRL, and cortisol. Attributes of pulsatile GH release were assessed by 3 independent algorithms. MK-677 administration for 2 weeks increased GH concentrations in a dose-dependent manner, with 25 mg/day increasing mean 24-h GH concentration 97 +/- 23% (mean +/- SE; P < 0.05 vs. baseline). This increase was due to an enhancement of preexisting pulsatile GH secretion. GH pulse height and interpulse nadir concentrations increased significantly without significant changes in the number of pulses. With 25 mg/day MK-677 treatment, mean serum IGF-I concentrations increased into the normal range for young adults (141 +/- 21 microgram/L at baseline, 219 +/- 21 micrograms/L at 2 weeks, and 265 +/- 29 micrograms/L at 4 weeks; P < 0.05). MK-677 produced significant increases in fasting glucose (5.4 +/- 0.3 to 6.8 +/- 0.4 mmol/L at 4 weeks; P < 0.01 vs. baseline) and IGF-binding protein-3. Circulating cortisol concentrations did not change, and PRL concentrations increased 23%, but remained within the normal range. Once daily treatment of older people with oral MK-677 for up to 4 weeks enhanced pulsatile GH release, significantly increased serum GH and IGF-I concentrations, and, at a dose of 25 mg/day, restored serum IGF-I concentrations to those of young adults.
Numerous physiological factors modulate GH secretion, but these variables are not independent of one another. We studied 40 younger (20-29 yr.; 21 men and 19 women) and 62 older (57-80 yr.; 35 men and 27 women) adults to determine the contributions of several demographic and physiological factors to the variability in integrated 24-h GH concentrations. Serum GH was measured every 10 min for 24 h in an enhanced sensitivity chemiluminescence assay. The predictor variables included: age group (young or old), gender, abdominal visceral fat (by computed tomography), total body fat mass and percentage body fat by dual-energy x-ray absorptiometry, serum IGF-I, fasting serum insulin, 24-h mean estradiol and testosterone, and peak oxygen uptake by graded exercise (treadmill) testing. Multiple ordinary least squares regression analysis was used to quantitatively assess the individual contribution that each predictive measure made to explain the variability among values of integrated 24-h GH concentrations while in the presence of the remaining predictors. The model explained 65% of the variance in integrated 24-h GH concentrations. Abdominal visceral fat (P < 0.002) and fasting insulin (P < 0.008) were consistently important predictors of integrated 24-h GH concentrations independent of age group, gender, and all other predictor variables. Although serum IGF-I was an important overall predictor of integrated 24-h GH concentrations (P = 0.002), this relationship was present only in the young subjects and was modulated by gender. The remaining variables failed to contribute significantly to the model. We conclude that abdominal visceral fat and fasting insulin are important predictors of integrated 24-h GH concentrations in healthy adults, independent of age and gender. Serum IGF-I is an important predictor of integrated 24-h GH concentrations in young but not older subjects. Bidirectional feedback between each of these three factors and GH secretion may account for the strong relationships observed.
Radiation-induced GH neurosecretory dysfunction either does not exist or is a very rare phenomenon in irradiated adult cancer survivors. The normality of physiological GH secretion in the context of reduced maximum somatotroph reserve suggests compensatory overdrive of the partially damaged somatotroph axis and constitutes a relative argument against somatotroph dysfunction being explained purely by hypothalamic damage with secondary atrophy due to GHRH deficiency. It is therefore possible that radiation in doses less than 40 Gy causes dual damage to both the pituitary and the hypothalamus.
These results provide further evidence of an age-dependent decline in circulating acyl-ghrelin levels, which might play a role both in the decline of GH and in the anorexia of aging. Our data also suggest that with normal aging, endogenous acyl-ghrelin levels are less tightly linked to GH regulation.
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