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Division of Endocrinology (F.B., C.Ga., A.J.v.d.L.), Department of Internal Medicine, Erasmus University of Rotterdam, The Netherlands; Division of Endocrinology and Metabolism, Department of Internal Medicine (C.Go., F.P., E.G.), Department of Biomedical Sciences and Oncology (M.P.); Department of Anatomy, Pharmacology and Forensic Medicine (G.M.); University of Turin, Italy; and TheraTechnologies (T.A.), Quebec, Canada
Address all correspondence and requests for reprints to: Ezio Ghigo, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Torino, Italy. E-mail: ezio.ghigo{at}unito.it.
Abstract
Ghrelin possesses strong GH-releasing activity but also other endocrine activities including stimulation of PRL and ACTH secretion, modulation of insulin secretion and glucose metabolism. It is assumed that the GH secretagogue (GHS) receptor (GHS-R) 1a mediates ghrelin actins provided its acylation in Serine 3; in fact, acylated ghrelin only is able to exert endocrine activities. Acylated ghrelin (AG) is present in serum at a 2.5 fold lower concentration than unacylated ghrelin (UAG). UAG, however, is not biologically inactive; it shares with AG some non-endocrine actions like cardiovascular effects, modulation of cell proliferation and even some influence on adipogenesis. Thus, these actions are likely to be mediated by GHS-R subtypes able to bind ghrelin independently of its acylation. In order to further clarify whether UAG is really devoid of any endocrine action, we studied the interaction of the combined administration of AG and UAG (1.0 µg/kg iv) in 6 normal young volunteers (age [mean ± SE]: 25.4 ± 1.2 yr; BMI: 22.3 ± 1.0 kg/m2). As expected, AG induced marked increase (p < 0.01) in circulating GH, PRL, ACTH and cortisol levels. AG administratioin was also followed by a decrease in insulin levels (–285.4 ± 64.8 mU*min/l; p < 0.05) and an increase in plasma glucose levels (1068.4 ± 390.4 mg*min/dl; p < 0.01). UAG alone did not induce any change in these parameters. UAG also failed to modify the GH, PRL, ACTH and cortisol responses to AG. However, when UAG was co-administered together with AG, no significant change in insulin (–0.5 ± 40.9 mU*min/l) and glucose levels (455.9 ± 88.3 mg*min/dl) was recorded anymore, indicating that the insulin and glucose response to AG has been abolished by UAG. In conclusion, non-acylated ghrelin does not affect the GH, PRL, and ACTH response to acylated ghrelin but is able to antagonize the effects of acylated ghrelin on insulin secretion and glucose levels. These findings indicate that unacylated ghrelin is metabolically active and is likely to counterbalance the influence of acylated ghrelin on insulin secretion and glucose metabolism. As GHS-R1a is not bound by unacylated ghrelin, these findings suggest that GHS receptor subtypes mediate the metabolic actions of both acylated and unacylated ghrelin.
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