Central ghrelin production does not substantially contribute to systemic ghrelin concentrations: a study in two subjects with active acromegaly

INTRODUCTION: In an animal model of acromegaly (PEPCK-hGH transgenic mice), low systemic levels of ghrelin have been observed compared with normal mice. We hypothesized that systemic circulating ghrelin levels are also decreased in humans with active acromegaly and that the contribution of central ghrelin production to systemic ghrelin levels is minimal. OBJECTIVES: The aim of the present study was to investigate, in two subjects with active acromegaly, whether there are differences between systemic ghrelin levels and ghrelin concentrations in the petrosal sinus. DESIGN: We measured systemic and central ghrelin levels in these two acromegalic patients by bilateral simultaneous inferior petrosal sinus sampling. Central and systemic blood samples were drawn before and 1, 5, 10, 15 and 20 min after stimulation with GH-releasing hormone (GHRH). Ghrelin was measured with a commercially available radioimmunoassay. RESULTS: In one acromegalic subject, the baseline systemic and central ghrelin levels were within the same range as in two non-acromegalic obese subjects. No gradient could be observed between central and systemic ghrelin concentrations. Stimulation with GHRH did not change the ghrelin concentrations in this patient. In the other acromegalic subject, the systemic ghrelin levels were also in the same range as in two non-acromegalic obese subjects. However, in this subject, baseline ghrelin concentrations in the right inferior petrosal vein were considerably lower than the systemic ghrelin concentrations, indicating a peripheral over central gradient. Administration of GHRH induced a significant rise in central ghrelin concentrations in the right inferior petrosal vein. Ghrelin levels in the left inferior petrosal vein and systemic ghrelin levels were in the normal range and GHRH stimulation did not change these concentrations. CONCLUSIONS: The absence of a central over peripheral ghrelin gradient in these two acromegalics indicated that circulating ghrelin is mainly produced peripherally. Circulating systemic ghrelin levels were not decreased in these two subjects with active acromegaly

Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans

Objective: To clarify the metabolic effects of an overnight i.v. infusion of unacylated ghrelin (UAG) in humans. UAG exerts relevant metabolic actions, likely mediated by a still unknown ghrelin receptor subtype, including effects on β-cell viability and function, insulin secretion and sensitivity, and glucose and lipid metabolism. Design: We studied the effects of a 16-h infusion (from 2100 to 1300 h) of UAG (1.0 μg/kg per h) or saline in eight normal subjects (age (mean±S.E.M.), 29.6±2.4 years; body mass index (BMI), 22.4±1.7 kg/m2), who were served, at 2100 and 0800 h respectively, with isocaloric balanced dinner and breakfast. Glucose, insulin, and free fatty acid (FFA) levels were measured every 20 min. Results: In comparison with saline, UAG induced significant (P<0.05) changes in glucose, insulin, and FFA profiles. UAG infusion decreased glucose area under the curve (AUC) values by 10% (UAG0-960 min: 79.0±1.7×10 3 mg/dl per min vs saline0-960 min: 87.5±3. 8×103 mg/dl per min) and the AUC at night by 14% (UAG 180-660 min: 28.4±0.5×103 mg/dl per min vs saline180-660 min: 33.2±1.1×103 mg/dl per min). The overall insulin AUC was not significantly modified by UAG infusion; however, insulin AUC observed after meals was significantly increased under the exposure to UAG with respect to saline at either dinner or breakfast. The FFA AUC values were decreased by 52% under the exposure to UAG in comparison with saline (UAG0-960 min: 0.3±0.02×103 mEq/l per min vs saline0-960 min: 0.6±0.05×103 mEq/l per min). Conclusions: Exposure to the i.v. administration of UAG improves glucose metabolism and inhibits lipolysis in healthy volunteers. Thus, in contrast to the diabetogenic action of AG, UAG displays hypoglycemic properties

Cortistatin-17 and -14 exert the same endocrine activities as somatostatin in humans

Cortistatin (CST) is a neuropeptide, which binds with high affinity all somatostatin (SS) receptor subtypes and shows high structural homology with SS itself. A receptor specific for CST only, i.e., not recognized by SS, has been recently described in agreement with data reporting that not all CST actions are shared by SS. Interestingly, CST but not SS also binds ghrelin receptor (GHS-R1a) in vitro, suggesting a potential interplay between CST and ghrelin system. The aim of this study was to investigate in humans the endocrine and metabolic activities of human CST-17 in comparison with rat CST-14 that has previously been shown to exert the same endocrine actions of SS in healthy volunteers. To this aim, in six healthy male volunteers (age [median, 3rd-97th centiles]: 28.5; 23.6-34.3 years; Body Mass Index: 23.5; 21.0-25.1 kg/m2), we studied the effects of human CST-17 (2.0 μg/kg/h iv over 120 min), rat CST-14 (2.0 μg/kg/h iv over 120 min) and SS-14 (2.0 μg/kg/h iv over 120 min) on: (a) spontaneous GH, ACTH, PRL, cortisol, insulin and glucose levels; (b) the GH responses to GHRH (1.0 μg/kg iv at 0 min); (c) the GH, PRL, ACTH, cortisol, insulin and glucose responses to ghrelin (1.0 μg/kg iv at 0 min). CST-17 inhibited (p<0.01) basal GH secretion to the same extent of CST-14 and SS-14. Spontaneous PRL, ACTH and cortisol secretion were not significantly modified by CST-17, CST-14 or SS-14. CST-17 as well as CST-14 and SS-14 also inhibited (p<0.05) spontaneous insulin secretion to a similar extent. None of these peptides modified glucose levels. The GH response to GHRH was inhibited to the same extent by CST-17 (p<0.01), CST-14 (p<0.01) and SS-14 (p<0.05). The ghrelin-induced GH response was higher than that elicited by GHRH (p<0.01) and inhibited by CST-17 (p<0.05) as well as by CST-14 (p<0.05) and SS-14 (p<0.01). The PRL, ACTH and cortisol responses to ghrelin were unaffected by CST-17, CST-14 or SS-14. On the other hand, the inhibitory effect of ghrelin on insulin levels was abolished by CST-17, CST-14 or SS-14 (p<0.05) that, in turn, did not modify the ghrelin-induced increase in glucose levels. In conclusion, this study demonstrates that human CST-17 and rat CST-14 exert the same endocrine activities of SS in humans. The endocrine actions of human and rat CST therefore are likely to reflect activation of classical SS receptors

Ghrelin drives GH secretion during fasting in man

OBJECTIVES: In humans, fasting leads to elevated serum GH concentrations. Traditionally, changes in hypothalamic GH-releasing hormone and somatostatin release are considered as the main mechanisms that induce this elevated GH secretion during fasting. Ghrelin is an endogenous ligand of the GH secretagogue receptor and is synthesized in the stomach. As ghrelin administration in man stimulates GH release, while serum ghrelin concentrations are elevated during fasting in man, this increase in ghrelin levels might be another mechanism whereby fasting results in stimulation of GH release. DESIGN AND SUBJECTS: In ten healthy non-obese males we performed a double-blind placebo-controlled crossover study comparing fasting with and fasting without GH receptor blockade. GH, ghrelin, insulin, glucose and free fatty acids were assessed. RESULTS: While ghrelin levels do not vary considerably in the fed state, fasting rapidly induced a diurnal rhythm in ghrelin concentrations. These changes in serum ghrelin concentrations during fasting were followed by similar, profound changes in serum GH levels. The rapid development of a diurnal ghrelin rhythm could not be explained by changes in insulin, glucos