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

Riccarda Granata, Fabio Settanni, Luigi Biancone, Letizia Trovato, Rita Nano, Federico Bertuzzi, Silvia Destefanis, Marta Annunziata, Monica Martinetti, Filomena Catapano, Corrado Ghè, Jorgen Isgaard, Mauro Papotti, Ezio Ghigo, Giampiero Muccioli

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Among its pleiotropic actions, ghrelin modulates insulin secretion and glucose metabolism. Herein we investigated the role of ghrelin in pancreatic β-cell proliferation and apoptosis induced by serum starvation or interferon (IFN)-γ/TNF-α, whose synergism is a major cause for β-cell destruction in type I diabetes. HIT-T15 β-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 Gαs protein and prevented serum starvation- and IFN-γ/TNF-α-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 β-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 β-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.

Original languageEnglish
Pages (from-to)512-529
Number of pages18
Issue number2
Publication statusPublished - Feb 2007


ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

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