Journal
DIABETES
Volume 60, Issue 9, Pages 2315-2324Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db11-0368
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Funding
- JKA through KEIRIN RACE
- Japan Society for the Promotion of Science
- Salt Science Research Foundation [09C5, 10C5]
- Pharmacological Research Foundation, Tokyo
- Takeda Science Foundation
- Swedish Research Council
- Swedish Diabetes Association
- Novo Nordisk Foundation
- European Foundation for the Study of Diabetes/Merck Sharp and Dohme (EFSD/MSD)
- Family Ernfors Foundation
- O.E. and Edla Johanssons Scientific Foundation
- Grants-in-Aid for Scientific Research [23591320] Funding Source: KAKEN
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OBJECTIVE-Ghrelin reportedly restricts insulin release in islet beta-cells via the G alpha(i2) subtype of G-proteins and thereby regulates glucose homeostasis. This study explored whether ghrelin regulates cAMP signaling and whether this regulation induces insulinostatic cascade in islet beta-cells. RESEARCH DESIGN AND METHODS-Insulin release was measured in rat perfused pancreas and isolated islets and cAMP production in isolated islets. Cytosolic cAMP concentrations ([cAMP](i)) were monitored in mouse MIN6 cells using evanescent-wave fluorescence imaging. In rat single beta-cells, cytosolic protein kinase-A activity ([PKA](i)) and Ca2+ concentration ([Ca2+](i)) were measured by DR-II and fura-2 microfluorometry, respectively, and whole cell currents by patch-clamp technique. RESULTS-Ghrelin suppressed glucose (8.3 mmol/L)-induced insulin release in rat perfused pancreas and isolated islets, and these effects of ghrelin were blunted in the presence of cAMP analogs or adenylate cyclase inhibitor. Glucose-induced cAMP production in isolated islets was attenuated by ghrelin and enhanced by ghrelin receptor antagonist and anti-ghrelin antiserum, which counteract endogenous islet-derived ghrelin. Ghrelin inhibited the glucose-induced [cAMP](i) elevation and [PKA](i) activation in MIN6 and rat beta-cells, respectively. Furthermore, ghrelin potentiated voltage-dependent K+ (Kv) channel currents without altering Ca2+ channel currents and attenuated glucose-induced [Ca2+](i) increases in rat beta-cells in a PKA-dependent manner. CONCLUSIONS-Ghrelin directly interacts with islet beta-cells to attenuate glucose-induced cAMP production and PKA activation, which lead In activation of Kv channels and suppression of glucose-induced [Ca2+](i) increase and insulin release. Diabetes 60:2315-2324, 2011
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