Abstract
The aim of this study is to describe a potential modulatory effect of acute acylated ghrelin (AG) administration on the glucose, insulin, and free fatty acids (FFA) responses to salbutamol (SALBU). Six healthy young male volunteers underwent the following four testing sessions in random order at least 7 days apart: (a) acute AG administration (1.0 μg/kg i.v. as bolus at 0′); (b) SALBU infusion (0.06 μg/kg/min i.v. from −15′ to +45′); (c) SALBU infusion + AG; and (d) isotonic saline infusion. Blood samples for glucose, insulin, and FFA levels were collected every 15 min. As expected, with respect to saline, SALBU infusion induced a remarkable increase in glucose (10.8 ± 5.6 mmol/l × min; P < 0.05), insulin (2436.8 ± 556.9 pmol/l × min; P < 0.05), and FFA (18.9 ± 4.5 mmol/l × min; P < 0.01) levels. A significant increase in glucose (7.4 ± 3.9 mmol/l × min; P < 0.05) and FFA levels (10.0 ± 2.8 mmol/l × min; P < 0.01) without significant variations in insulin levels were recorded after AG administration. Interestingly, the hyperglycemic effect of AG appeared to be significantly potentiated during SALBU infusion (26.7 ± 4.8 mmol/l × min; P < 0.05). On the other hand, the stimulatory effect of SALBU on insulin and FFA was not significantly modified by AG administration. The results of this study show that acute AG administration has a synergic effect with β2-adrenergic receptor activation by SALBU on blood glucose increase, suggesting that their pharmacological hyperglycemic action takes place via different mechanisms. On the other hand, AG has a negligible influence on the other pharmacological metabolic effects of SALBU infusion.
Similar content being viewed by others
References
M. Kojima, H. Hosoda, H. Matsuo, K. Kangawa, Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol. Metab. 12, 118–122 (2001)
S. Gnanapavan, B. Kola, S.A. Bustin, D.G. Morris, P. McGee, P. Fairclough, S. Bhattacharya, R. Carpenter, A.B. Grossman, M. Korbonits, The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J. Clin. Endocrinol. Metab. 87, 2988 (2002)
C. De Vriese, C. Delporte, Influence of ghrelin on food intake and energy homeostasis. Curr. Opin. Clin. Nutr. Metab. Care 10, 615–619 (2007)
H. Kirchner, K.M. Heppner, M.H. Tschöp, The role of ghrelin in the control of energy balance. Handb. Exp. Pharmacol. 161–184 (2012)
M.A. van Baak, The peripheral sympathetic nervous system in human obesity. Obes. Rev. 2, 3–14 (2001)
J. Robidoux, T.L. Martin, S. Collins, Beta-adrenergic receptors and regulation of energy expenditure: a family affair. Annu. Rev. Pharmacol. Toxicol. 44, 297–323 (2004)
H. Imura, Y. Kato, M. Ikeda, M. Morimoto, M. Yawata, Effect of adrenergic-blocking or -stimulating agents on plasma growth hormone, immunoreactive insulin, and blood free fatty acid levels in man. J. Clin. Invest. 50, 1069–1079 (1971)
P.D. Gluckman, The development of beta-adrenergic mediated inhibition of growth hormone secretion in the ovine fetus. J. Dev. Physiol. 4, 207–214 (1982)
G. Muccioli, N. Pons, C. Ghè, F. Catapano, R. Granata, E. Ghigo, Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1a growth hormone secretagogue receptor. Eur. J. Pharmacol. 498, 27–35 (2004)
M.T. Bluet-Pajot, D. Durand, F. Mounier, C. Schaub, C. Kordon, Interaction of beta-adrenergic agonists and antagonists with the stimulation of growth hormone release induced by clonidine or by morphine in the rat. J. Endocrinol. 94, 327–331 (1982)
H.S. Park, E.S. Shin, J.E. Lee, Genotypes and haplotypes of beta2-adrenergic receptor and parameters of the metabolic syndrome in Korean adolescents. Metabolism 57, 1064–1070 (2008)
J.P. Palmer, J. Halter, P.L. Werner, Differential effect of isoproterenol on acute glucagon and insulin release in man. Metabolism 28, 237–240 (1979)
P. Kuusela, S. Rehnmark, A. Jacobsson, B. Cannon, J. Nedergaard, Adrenergic stimulation of lipoprotein lipase gene expression in rat brown adipocytes differentiated in culture: mediation via beta3- and alpha1-adrenergic receptors. Biochem. J. 321(Pt 3), 759–767 (1997)
E. Ghigo, E. Arvat, L. Gianotti, J. Ramunni, M. Maccario, F. Camanni, Interaction of salbutamol with pyridostigmine and arginine on both basal and GHRH-stimulated GH secretion in humans. Clin. Endocrinol. (Oxf.) 40, 799–802 (1994)
E. Arvat, L. Gianotti, J. Ramunni, L. DiVito, R. Deghenghi, F. Camanni, E. Ghigo, Influence of beta-adrenergic agonists and antagonists on the GH-releasing effect of hexarelin in man. J. Endocrinol. Invest. 19, 25–29 (1996)
T.-J. Zhao, I. Sakata, R.L. Li, G. Liang, J.A. Richardson, M.S. Brown, J.L. Goldstein, J.M. Zigman, Ghrelin secretion stimulated by 1-adrenergic receptors in cultured ghrelinoma cells and in fasted mice. Proc. Natl. Acad. Sci. 107, 15868–15873 (2010)
J. Gagnon, Y. Anini, Insulin and norepinephrine regulate ghrelin secretion from a rat primary stomach cell culture. Endocrinology 153, 3646–3656 (2012)
A. Baragli, C. Ghè, E. Arnoletti, R. Granata, E. Ghigo, G. Muccioli, Acylated and unacylated ghrelin attenuate isoproterenol-induced lipolysis in isolated rat visceral adipocytes through activation of phosphoinositide 3-kinase γ and phosphodiesterase 3B. Biochim. Biophys. Acta 1811, 386–396 (2011)
E. Adeghate, A.S. Ponery, Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. J. Neuroendocrinol. 14, 555–560 (2002)
D.H. St-Pierre, A. Benso, E. Gramaglia, F. Prodam, B. Lucatello, V. Ramella-Gigliardi, I. Olivetti, M. Tomelini, F. Broglio, The metabolic response to the activation of the beta-adrenergic receptor by salbutamol is amplified by acylated ghrelin. J. Endocrinol. Invest. 33, 363–367 (2010)
A.C. Heijboer, A.M. van den Hoek, E.T. Parlevliet, L.M. Havekes, J.A. Romijn, H. Pijl, E.P.M. Corssmit, Ghrelin differentially affects hepatic and peripheral insulin sensitivity in mice. Diabetologia 49, 732–738 (2006)
T.R. Castañeda, J. Tong, R. Datta, M. Culler, M.H. Tschöp, Ghrelin in the regulation of body weight and metabolism. Front. Neuroendocrinol. 31, 44–60 (2010)
M. Murata, Y. Okimura, K. Iida, M. Matsumoto, H. Sowa, H. Kaji, M. Kojima, K. Kangawa, K. Chihara, Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. J. Biol. Chem. 277, 5667–5674 (2002)
C. Gauna, P.J.D. Delhanty, L.J. Hofland, J.A. Janssen, F. Broglio, R.J.M. Ross, E. Ghigo, A.J. van der Lely, Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. J. Clin. Endocrinol. Metab. 90, 1055–1060 (2005)
L.H. Philipson, β-Agonists and metabolism. J. Allergy Clin. Immunol. 110, S313–S317 (2002)
R.J. Lacey, N.S. Berrow, N.J.M. London, S.P. Lake, R.F. James, J.H.B. Scarpello, N.G. Morgan, Differential effects of β-adrenergic agonists on insulin secretion from pancreatic islets isolated from rat and man. J. Mol. Endocrinol. 5, 49–54 (1990)
A. Loubatières, M.M. Mariani, G. Sorel, L. Savi, The action of β-adrenergic blocking and stimulating agents on insulin secretion. Characterization of the type of β receptor. Diabetologia 7(3), 127–132 (1971)
E. Cipolletta, A. Campanile, G. Santulli, E. Sanzari, D. Leosco, P. Campiglia, B. Trimarco, G. Iaccarino, The G protein coupled receptor kinase 2 plays an essential role in beta-adrenergic receptor-induced insulin resistance. Cardiovasc. Res. 84, 407–415 (2009)
M. Lafontan, M. Berlan, Fat cell adrenergic receptors and the control of white and brown fat cell function. J. Lipid Res. 34, 1057–1091 (1993)
F. Broglio, E. Arvat, A. Benso, C. Gottero, G. Muccioli, M. Papotti, A.J. van der Lely, R. Deghenghi, E. Ghigo, Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J. Clin. Endocrinol. Metab. 86, 5083–5086 (2001)
T. Yada, K. Dezaki, H. Sone, M. Koizumi, B. Damdindorj, M. Nakata, M. Kakei, Ghrelin regulates insulin release and glycemia: physiological role and therapeutic potential. Curr. Diabetes Rev. 4, 18–23 (2008)
W. An, Y. Li, G. Xu, J. Zhao, X. Xiang, L. Ding, J. Li, Y. Guan, X. Wang, C. Tang, X. Li, M. Mulholland, W. Zhang, Modulation of ghrelin O-acyltransferase expression in pancreatic islets. Cell Physiol. Biochem 26, 707–716 (2010)
K. Dezaki, Ghrelin function in insulin release and glucose metabolism. Endocr. Dev. 25, 135–143 (2013)
P.-J. Verhulst, I. Depoortere, Ghrelin’s second life: from appetite stimulator to glucose regulator. World J. Gastroenterol. 18, 3183–3195 (2012)
P. Lucidi, G. Murdolo, C. Di Loreto, N. Parlanti, A. De Cicco, C. Fatone, C. Taglioni, C. Fanelli, F. Broglio, E. Ghigo, G.B. Bolli, F. Santeusanio, P. De Feo, Metabolic and endocrine effects of physiological increments in plasma ghrelin concentrations. Nutr. Metab. Cardiovasc. Dis. 15, 410–417 (2005)
J. Tong, R.L. Prigeon, H.W. Davis, M. Bidlingmaier, M.H. Tschöp, D. D’Alessio, Physiologic concentrations of exogenously infused ghrelin reduces insulin secretion without affecting insulin sensitivity in healthy humans. J. Clin. Endocrinol. Metab. 98, 2536–2543 (2013)
Acknowledgments
This study was supported by the European FP6 Project DIABESITY, the Ministero dell’ Università e della Ricerca Scientifica, the University of Turin, SMEM Foundation of Turin.
Conflict of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Benso, A., Gramaglia, E., Olivetti, I. et al. Acute effects of acylated ghrelin on salbutamol-induced metabolic actions in humans. Endocrine 48, 937–941 (2015). https://doi.org/10.1007/s12020-014-0343-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-014-0343-6