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

被引：256

作者：

Granata, Riccarda ^{[1
]}

Settanni, Fabio ^{[1
]}

Biancone, Luigi ^{[1
]}

Trovato, Letizia ^{[1
]}

Nano, Rita ^{[1
]}

Bertuzzi, Federico ^{[1
]}

Destefanis, Silvia ^{[1
]}

Annunziata, Marta ^{[1
]}

Martinetti, Monica ^{[1
]}

Catapano, Filomena ^{[1
]}

Ghe, Corrado ^{[1
]}

Isgaard, Jorgen ^{[1
]}

Papotti, Mauro ^{[1
]}

Ghigo, Ezio ^{[1
]}

Muccioli, Giampiero ^{[1
]}

机构：

[1] Univ Turin, Dept Internal Med, Div Endocrinol & Metab, Lab Mol & Cellular Endocrinol, I-10126 Turin, Italy

来源：

ENDOCRINOLOGY | 2007年 / 148卷 / 02期

关键词：

D O I：

10.1210/en.2006-0266

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 G alpha(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 apoptosis in human islets of Langerhans. These expressed GRLN-R but showed also UAG and AG binding sites. Our data demonstrate that AG and UAG promote survival of both beta-cells and human islets. These effects are independent of GRLN-R, are likely mediated by AG/UAG binding sites, and involve cAMP/PKA, ERK1/2, and PI3K/Akt.

引用

页码：512 / 529

页数：18

共 84 条

[1] Would blockage of cytokines improve the outcome of pancreatic islet transplantation? [J].