Acylated and Unacylated Ghrelin Promote Proliferation and Inhibit Apoptosis of Pancreatic β-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

作者：Riccarda Granata, Fabio Settanni, Luigi Biancone, Letizia Trovato, Rita Nano, Federico Bertuzzi, Silvia Destefanis, Marta Annunziata, M. Martinetti, Filomena Catapano, Corrado Ghé, Jörgen Isgaard, Mauro Papotti, Ezio Ghigo, Giampiero Muccioli · 发表于：Endocrinology · 年份：2006 · DOI：10.1210/en.2006-0266 · 被引用次数：294 · 研究领域：Regulation of Appetite and Obesity、Pancreatic function and diabetes、Adipose Tissue and Metabolism

Among its pleiotropic actions, ghrelin modulates insulin secretion and glucose metabolism. Herein we investigated the role of ghrelin in pancreatic beta-cell proliferation and apoptosis induced by serum starvation or interferon (IFN)-gamma/TNF-alpha, whose synergism is a major cause for beta-cell destruction in type I diabetes. HIT-T15 beta-cells expressed ghrelin but not ghrelin receptor (GRLN-R), which binds acylated ghrelin (AG) only. However, both unacylated ghrelin (UAG) and AG recognized common high-affinity binding sites on these cells. Either AG or UAG stimulated cell proliferation through Galpha(s) protein and prevented serum starvation- and IFN-gamma/TNF-alpha-induced apoptosis. Antighrelin antibody enhanced apoptosis in either the presence or absence of serum but not cytokines. AG and UAG even up-regulated intracellular cAMP. Blockade of adenylyl cyclase/cAMP/protein kinase A signaling prevented the ghrelin cytoprotective effect. AG and UAG also activated phosphatidyl inositol 3-kinase (PI3K)/Akt and ERK1/2, whereas PI3K and MAPK inhibitors counteracted the ghrelin antiapoptotic effect. Furthermore, AG and UAG stimulated insulin secretion from HIT-T15 cells. In INS-1E beta-cells, which express GRLN-R, AG and UAG caused proliferation and protection against apoptosis through identical signaling pathways. Noteworthy, both peptides inhibited cytokine-induced NO increase in either HIT-T15 or INS-1E cells. Finally, they induced cell survival and protection against apopto...