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Diabetes. 2011 Sep;60(9):2315-24. doi: 10.2337/db11-0368. Epub 2011 Jul 25.

Ghrelin attenuates cAMP-PKA signaling to evoke insulinostatic cascade in islet β-cells.

Author information

1
Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan. dezaki@jichi.ac.jp

Abstract

OBJECTIVE:

Ghrelin reportedly restricts insulin release in islet β-cells via the Gα(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 β-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 β-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 β-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 β-cells in a PKA-dependent manner.

CONCLUSIONS:

Ghrelin directly interacts with islet β-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.

PMID:
21788571
PMCID:
PMC3161328
DOI:
10.2337/db11-0368
[Indexed for MEDLINE]
Free PMC Article
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