Background: Ghrelin has been reported to be the natural ligand of growth hormone (GH) secretagogue receptor, and it is known that exogenous ghrelin administration strongly stimulates GH release in humans. However, the effects of endogenous ghrelin on GH secretion and changes in ghrelin levels during dynamic changes in GH levels are not well understood. Methods: Therefore, we measured circulating acylated ghrelin concentrations during oral glucose tolerance tests (OGTTs) in patients with active acromegaly (AA, n = 9) and in age/sex/BMI-matched group A controls (n = 12), and during insulin tolerance testing (ITT) in patients with GH deficiency (GHD, n = 10) and in group B controls (n = 10). Plasma acylated ghrelin, serum GH, insulin and glucose levels were measured during each test. Results: Fasting plasma ghrelin levels correlated negatively with serum insulin levels in both group A and B controls (r = –0.665; p < 0.05) but not in patients with AA or GHD. During OGTTs, circulating ghrelin levels decreased significantly with a nadir at 30 min in both patients with AA (p < 0.05) and group A controls (p < 0.01). Also, ITTs were followed by a significant decrease in circulating ghrelin levels with a nadir at 30 min in patients with GHD (p < 0.05) and in group B controls (p < 0.05). Conclusion: The results of the study show that at baseline acylated ghrelin levels do not differ with respect to the GH status (GH excess or GH deficiency) and, furthermore, the suppression of acylated ghrelin levels during OGTT or ITT is independent of the GH response to the tests.

Keywords:
Ghrelin secretion, Growth hormone deficiency, Active acromegaly
1.
Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K: Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656–660.
2.
Dickson SL, Luckman SM: Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide 6. Endocrinology 1997;138:771–777.
3.
Guillaume V, Magnan E, Cataldi M, Dutour A, Sauze N, Renard M, Razafindraibe H, Conte-Devolx B, Deghenghi R, Lenaerts V: Growth hormone (GH)-releasing hormone secretion is stimulated by a new GH-releasing hexapeptide in sheep. Endocrinology 1994;135:1073–1076.
4.
Takaya K, Ariyasu H, Kanamoto N, Iwakura H, Yoshimoto A, Harada M, Mori K, Komatsu Y, Usui T, Shimatsu A, Ogawa Y, Hosoda K, Akamizu T, Kojima M, Kangawa K, Nakao K: Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000;85:4908–4911.
5.
Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS: A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001;50:1714–1719.
6.
Tschop M, Smiley DL, Heiman ML: Ghrelin induces adiposity in rodents. Nature 2000;407:908–913.
7.
Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR: Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 2001;86:5992.
8.
Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ: Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002;346:1623–1630.
9.
Otto B, Cuntz U, Fruehauf E, Wawarta R, Folwaczny C, Riepl RL, Heiman ML, Lehnert P, Fichter M, Tschop M: Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur J Endocrinol 2001;145:669–673.
10.
Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML: Circulating ghrelin levels are decreased in human obesity. Diabetes 2001;50:707–709.
11.
Lucidi P, Murdolo G, Di Loreto C, De Cicco A, Parlanti N, Fanelli C, Santeusanio F, Bolli GB, De Feo P: Ghrelin is not necessary for adequate hormonal counterregulation of insulin-induced hypoglycemia. Diabetes 2002;51:2911–2914.
12.
Saad MF, Bernaba B, Hwu CM, Jinagouda S, Fahmi S, Kogosov E, Boyadjian R: Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab 2002;87:3997–4000.
13.
Eden Engstrom B, Burman P, Holdstock C, Karlsson FA: Effects of growth hormone (GH) on ghrelin, leptin, and adiponectin in GH-deficient patients. J Clin Endocrinol Metab 2003;88:5193–5198.
14.
Janssen JA, van der Toorn FM, Hofland LJ, van Koetsveld P, Broglio F, Ghigo E, Lamberts SW, van der Lely AJ: Systemic ghrelin levels in subjects with growth hormone deficiency are not modified by one year of growth hormone replacement therapy. Eur J Endocrinol 2001;145:711–716.
15.
Hotta M, Ohwada R, Katakami H, Shibasaki T, Hizuka N, Takano K: Plasma levels of intact and degraded ghrelin and their responses to glucose infusion in anorexia nervosa. J Clin Endocrinol Metab 2004;89:5707–5712.
16.
Broglio F, Gottero C, Prodam F, Gauna C, Muccioli G, Papotti M, Abribat T, van der Lely AJ, Ghigo E: Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans. J Clin Endocrinol Metab 2004;89:3062–3065.
17.
Cassoni P, Papotti M, Ghe C, Catapano F, Sapino A, Graziani A, Deghenghi R, Reissmann T, Ghigo E, Muccioli G: Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. J Clin Endocrinol Metab 2001;86:1738–1745.
18.
Thompson NM, Gill DA, Davies R, Loveridge N, Houston PA, Robinson IC, Wells T: Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology 2004;145:234–242.
19.
Akamizu T, Shinomiya T, Irako T, Fukunaga M, Nakai Y, Kangawa K: Separate measurement of plasma levels of acylated and desacyl ghrelin in healthy subjects using a new direct ELISA assay. J Clin Endocrinol Metab 2005;90:6–9.
20.
Arvat E, Di Vito L, Broglio F, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E: Preliminary evidence that ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest 2000;23:493–495.
21.
Di Vito L, Broglio F, Benso A, Gottero C, Prodam F, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Ghigo E, Arvat E: The GH-releasing effect of ghrelin, a natural GH secretagogue, is only blunted by the infusion of exogenous somatostatin in humans. Clin Endocrinol (Oxf) 2002;56:643–648.
22.
Cappiello V, Ronchi C, Morpurgo PS, Epaminonda P, Arosio M, Beck-Peccoz P, Spada A: Circulating ghrelin levels in basal conditions and during glucose tolerance test in acromegalic patients. Eur J Endocrinol 2002;147:189–194.
23.
Barkan AL, Dimaraki EV, Jessup SK, Symons KV, Ermolenko M, Jaffe CA: Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels. J Clin Endocrinol Metab 2003;88:2180–2184.
24.
Malik IA, English PJ, Ghatei MA, Bloom SR, MacFarlane IA, Wilding JP: The relationship of ghrelin to biochemical and anthropometric markers of adult growth hormone deficiency. Clin Endocrinol (Oxf) 2004;60:137–141.
25.
Muller AF, Lamberts SW, Janssen JA, Hofland LJ, Koetsveld PV, Bidlingmaier M, Strasburger CJ, Ghigo E, van der Lely AJ: Ghrelin drives GH secretion during fasting in man. Eur J Endocrinol 2002;146:203–207.
26.
Freda PU, Reyes CM, Conwell IM, Sundeen RE, Wardlaw SL: Serum ghrelin levels in acromegaly: effects of surgical and long-acting octreotide therapy. J Clin Endocrinol Metab 2003;88:2037–2044.
27.
Bengtsson BA, Brummer RJ, Eden S, Bosaeus I: Body composition in acromegaly. Clin Endocrinol (Oxf) 1989;30:121–130.
28.
Dall R, Kanaley J, Hansen TK, Moller N, Christiansen JS, Hosoda H, Kangawa K, Jorgensen JO: Plasma ghrelin levels during exercise in healthy subjects and in growth hormone-deficient patients. Eur J Endocrinol 2002;147:65–70.
29.
Qi X, Reed J, Englander EW, Chandrashekar V, Bartke A, Greeley GH Jr: Evidence that growth hormone exerts a feedback effect on stomach ghrelin production and secretion. Exp Biol Med (Maywood) 2003;228:1028–1032.
30.
Sun Y, Ahmed S, Smith RG: Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 2003;23:7973–7981.
31.
Vestergaard ET, Hansen TK, Nielsen S, Moller N, Christiansen JS, Jorgensen JO: Effects of GH replacement therapy in adults on serum levels of leptin and ghrelin: the role of lipolysis. Eur J Endocrinol 2005;153:545–549.
32.
Baldelli R, Bellone S, Castellino N, Petri A, Rapa A, Vivenza D, Bellone J, Broglio F, Ghigo E, Bona G: Oral glucose load inhibits circulating ghrelin levels to the same extent in normal and obese children. Clin Endocrinol (Oxf) 2006;64:255–259.
33.
Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S: Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 2002;87:240–244.
34.
Rudovich NN, Dick D, Moehlig M, Otto B, Spranger J, Rochlitz HJ, Ristow M, Tschoep M, Pfeiffer AF: Ghrelin is not suppressed in hyperglycemic clamps by gastric inhibitory polypeptide and arginine. Regul Pept 2005;127:95–99.
35.
Broglio F, Gottero C, Prodam F, Destefanis S, Gauna C, Me E, Riganti F, Vivenza D, Rapa A, Martina V, Arvat E, Bona G, van der Lely AJ, Ghigo E: Ghrelin secretion is inhibited by glucose load and insulin-induced hypoglycaemia but unaffected by glucagon and arginine in humans. Clin Endocrinol (Oxf) 2004;61:503–509.
36.
Arafat MA, Otto B, Rochlitz H, Tschop M, Bahr V, Mohlig M, Diederich S, Spranger J, Pfeiffer AF: Glucagon inhibits ghrelin secretion in humans. Eur J Endocrinol 2005;153:397–402.
37.
Tolle V, Bassant MH, Zizzari P, Poindessous-Jazat F, Tomasetto C, Epelbaum J, Bluet-Pajot MT: Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats. Endocrinology 2002;143:1353–1361.
38.
Brelje TC, Scharp DW, Lacy PE, Ogren L, Talamantes F, Robertson M, Friesen HG, Sorenson RL: Effect of homologous placental lactogens, prolactins, and growth hormones on islet B-cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy. Endocrinology 1993;132:879–887.
39.
Freemark M, Avril I, Fleenor D, Driscoll P, Petro A, Opara E, Kendall W, Oden J, Bridges S, Binart N, Breant B, Kelly PA: Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance. Endocrinology 2002;143:1378–1385.
40.
Foss MC, Paula FJ, Paccola GM, Piccinato CE: Peripheral glucose metabolism in human hyperprolactinaemia. Clin Endocrinol (Oxf) 1995;43:721–726.
41.
Ryan EA, Enns L: Role of gestational hormones in the induction of insulin resistance. J Clin Endocrinol Metab 1988;67:341–347.
© 2007 S. Karger AG, Basel
2006
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.