HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dezaki, K. Articles by Yada, T. Search for Related Content PubMed PubMed Citation Articles by Dezaki, K. Articles by Yada, T. Social Bookmarking                What's this?

Endogenous Ghrelin in Pancreatic Islets Restricts Insulin Release by Attenuating Ca²⁺ Signaling in ß-Cells

Implication in the Glycemic Control in Rodents

¹ Department of Physiology, Division of Integrative Physiology, Jichi Medical School, Kawachi, Tochigi, Japan
² Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan
³ Department of Internal Medicine, Division of Endocrinology, Diabetes Geriatric Medicine, Akita University School of Medicine, Akita, Japan
⁴ Second Department of Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan

Ghrelin, isolated from the human and rat stomach, is the endogenous ligand for the growth hormone (GH) secretagogue receptor, which is expressed in a variety of tissues, including the pancreatic islets. It has been shown that low plasma ghrelin levels correlates with elevated fasting insulin levels and type 2 diabetes. Here we show a physiological role of endogenous ghrelin in the regulation of insulin release and blood glucose in rodents. Acylated ghrelin, the active form of the peptide, was detected in the pancreatic islets. Counteraction of endogenous ghrelin by intraperitoneal injection of specific GH secretagogue receptor antagonists markedly lowered fasting glucose concentrations, attenuated plasma glucose elevation, and enhanced insulin responses during the glucose tolerance test (GTT). Conversely, intraperitoneal exogenous ghrelin GH-independently elevated fasting glucose concentrations, enhanced plasma glucose elevation, and attenuated insulin responses during GTT. Neither GH secretagogue receptor antagonist nor ghrelin affected the profiles of the insulin tolerance test. In isolated islets, GH secretagogue receptor blockade and antiserum against acylated ghrelin markedly enhanced glucose-induced increases in insulin release and intracellular Ca²⁺ concentration ([Ca²⁺]_i), whereas ghrelin at a relatively high concentration (10 nmol/l) suppressed insulin release. In single ß-cells, ghrelin attenuated glucose-induced first-phase and oscillatory [Ca²⁺]_i increases via the GH secretagogue receptor and in a pertussis toxin-sensitive manner. Ghrelin also increased tetraethylammonium-sensitive delayed outward K⁺ currents in single ß-cells. These findings reveal that endogenous ghrelin in islets acts on ß-cells to restrict glucose-induced insulin release at least partly via attenuation of Ca²⁺ signaling, and that this insulinostatic action may be implicated in the upward control of blood glucose. This function of ghrelin, together with inducing GH release and feeding, suggests that ghrelin underlies the integrative regulation of energy homeostasis.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. T. Ruohonen, U. Pesonen, N. Moritz, K. Kaipio, M. Roytta, M. Koulu, and E. Savontaus Transgenic Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons: A Novel Model of Increased Adiposity and Impaired Glucose Tolerance Diabetes, June 1, 2008; 57(6): 1517 - 1525. [Abstract] [Full Text] [PDF]

				W. P. Esler, J. Rudolph, T. H. Claus, W. Tang, N. Barucci, S.-E. Brown, W. Bullock, M. Daly, L. DeCarr, Y. Li, et al. Small-Molecule Ghrelin Receptor Antagonists Improve Glucose Tolerance, Suppress Appetite, and Promote Weight Loss Endocrinology, November 1, 2007; 148(11): 5175 - 5185. [Abstract] [Full Text] [PDF]

				H. Takahashi, Y. Kurose, M. Sakaida, Y. Suzuki, S. Kobayashi, T. Sugino, M. Kojima, K. Kangawa, Y. Hasegawa, and Y. Terashima Ghrelin differentially modulates glucose-induced insulin secretion according to feeding status in sheep J. Endocrinol., September 1, 2007; 194(3): 621 - 625. [Abstract] [Full Text] [PDF]

				K. Dezaki, M. Kakei, and T. Yada Ghrelin Uses G{alpha}i2 and Activates Voltage-Dependent K+ Channels to Attenuate Glucose-Induced Ca2+ Signaling and Insulin Release in Islet {beta}-Cells: Novel Signal Transduction of Ghrelin Diabetes, September 1, 2007; 56(9): 2319 - 2327. [Abstract] [Full Text] [PDF]

				C. Gauna, R. M. Kiewiet, J. A. M. J. L. Janssen, B. van de Zande, P. J. D. Delhanty, E. Ghigo, L. J. Hofland, A. P. N. Themmen, and A. J. van der Lely Unacylated ghrelin acts as a potent insulin secretagogue in glucose-stimulated conditions Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E697 - E704. [Abstract] [Full Text] [PDF]

				D. Kohno, M. Nakata, F. Maekawa, K. Fujiwara, Y. Maejima, M. Kuramochi, T. Shimazaki, H. Okano, T. Onaka, and T. Yada Leptin Suppresses Ghrelin-Induced Activation of Neuropeptide Y Neurons in the Arcuate Nucleus via Phosphatidylinositol 3-Kinase- and Phosphodiesterase 3-Mediated Pathway Endocrinology, May 1, 2007; 148(5): 2251 - 2263. [Abstract] [Full Text] [PDF]

				P. Pissios, U. Ozcan, E. Kokkotou, T. Okada, C. W. Liew, S. Liu, J. N. Peters, G. Dahlgren, J. Karamchandani, Y. C. Kudva, et al. Melanin Concentrating Hormone Is a Novel Regulator of Islet Function and Growth Diabetes, February 1, 2007; 56(2): 311 - 319. [Abstract] [Full Text] [PDF]

				R. Granata, F. Settanni, L. Biancone, L. Trovato, R. Nano, F. Bertuzzi, S. Destefanis, M. Annunziata, M. Martinetti, F. Catapano, et al. Acylated and Unacylated Ghrelin Promote Proliferation and Inhibit Apoptosis of Pancreatic {beta}-Cells and Human Islets: Involvement of 3',5'-Cyclic Adenosine Monophosphate/Protein Kinase A, Extracellular Signal-Regulated Kinase 1/2, and Phosphatidyl Inositol 3-Kinase/Akt Signaling Endocrinology, February 1, 2007; 148(2): 512 - 529. [Abstract] [Full Text] [PDF]

				X. Zhu, Y. Cao, K. Voodg, and D. F. Steiner On the Processing of Proghrelin to Ghrelin J. Biol. Chem., December 15, 2006; 281(50): 38867 - 38870. [Abstract] [Full Text] [PDF]

				K. Dezaki, H. Sone, M. Koizumi, M. Nakata, M. Kakei, H. Nagai, H. Hosoda, K. Kangawa, and T. Yada Blockade of Pancreatic Islet-Derived Ghrelin Enhances Insulin Secretion to Prevent High-Fat Diet-Induced Glucose Intolerance Diabetes, December 1, 2006; 55(12): 3486 - 3493. [Abstract] [Full Text] [PDF]

				P. Marzullo, A. Caumo, G. Savia, B. Verti, G. E. Walker, S. Maestrini, A. Tagliaferri, A. M. Di Blasio, and A. Liuzzi Predictors of Postabsorptive Ghrelin Secretion after Intake of Different Macronutrients J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 4124 - 4130. [Abstract] [Full Text] [PDF]

				J. M. Zigman and J. K. Elmquist In search of an effective obesity treatment: A shot in the dark or a shot in the arm? PNAS, August 29, 2006; 103(35): 12961 - 12962. [Full Text] [PDF]

				M. Suematsu, A. Katsuki, Y. Sumida, E. C Gabazza, S. Murashima, K. Matsumoto, N. Kitagawa, H. Akatsuka, Y. Hori, K. Nakatani, et al. Decreased circulating levels of active ghrelin are associated with increased oxidative stress in obese subjects Eur. J. Endocrinol., September 1, 2005; 153(3): 403 - 407. [Abstract] [Full Text] [PDF]