| First Author | Dezaki K | Year | 2011 |
| Journal | Diabetes | Volume | 60 |
| Issue | 9 | Pages | 2315-24 |
| PubMed ID | 21788571 | Mgi Jnum | J:187801 |
| Mgi Id | MGI:5438203 | Doi | 10.2337/db11-0368 |
| Citation | Dezaki K, et al. (2011) Ghrelin attenuates cAMP-PKA signaling to evoke insulinostatic cascade in islet beta-cells. Diabetes 60(9):2315-24 |
| abstractText | OBJECTIVE: Ghrelin reportedly restricts insulin release in islet beta-cells via the Galpha(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 Ca(2+) concentration ([Ca(2+)](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 Ca(2+) channel currents and attenuated glucose-induced [Ca(2+)](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 to activation of Kv channels and suppression of glucose-induced [Ca(2+)](i) increase and insulin release. |
