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

Implication in the Glycemic Control in Rodents

  1. Katsuya Dezaki1,
  2. Hiroshi Hosoda2,
  3. Masafumi Kakei3,
  4. Suzuko Hashiguchi14,
  5. Masatomo Watanabe1,
  6. Kenji Kangawa2 and
  7. Toshihiko Yada1
  1. 1Department of Physiology, Division of Integrative Physiology, Jichi Medical School, Kawachi, Tochigi, Japan
  2. 2Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka, Japan
  3. 3Department of Internal Medicine, Division of Endocrinology, Diabetes Geriatric Medicine, Akita University School of Medicine, Akita, Japan
  4. 4Second Department of Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
  1. Address correspondence and reprint requests to Toshihiko Yada, Department of Physiology, Division of Integrative Physiology, Jichi Medical School, Yakushiji 3311-1, Minamikawachi, Kawachi, Tochigi 329-0498, Japan. E-mail: tyada{at}jichi.ac.jp


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 β-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 β-cells. These findings reveal that endogenous ghrelin in islets acts on β-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.


    • Accepted August 23, 2004.
    • Received May 28, 2004.
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