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/tumor necrosis (TNF)-, whose synergism is of major cause for cell destruction in type I diabetes. HIT-T15 β cells expressed ghrelin but not ghrelin receptor (GRLN-R), that binds acylated ghrelin only. However, both unacylated ghrelin (UAG) as well as acylated ghrelin (AG) recognized common high affinity binding sites on these cells. Either AG or UAG stimulated cell proliferation through Gs protein and prevented serum starvation- and IFN-γ/TNF--induced apoptosis. Anti-ghrelin antibody enhanced apoptosis in either 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 ghrelin cytoprotective effect. AG and UAG also activated PI3K/Akt and ERK1/2, whereas PI3K and MAPK inhibitors counteracted ghrelin antiapoptotic effect. Further, AG and UAG stimulated insulin secretion from HIT-T15 cells. In INS-1E β cells, that express GRLN-R, AG and UAG caused proliferation and protection against apoptosis through identical signaling pathways. Finally, both peptides induced cell survival and protection against serum starvation- and cytokine-evoked apoptosis in human islets of Langerhans. These expressed GRLN-R but showed also binding sites recognizing UAG and AG. Our data demonstrate that AG and UAG promote survival of both β cells and human islets. These effects are independent of the presence of GRLN-R, are likely mediated by AG/UAG binding sites and involve cAMP/PKA, ERK1/2 and PI3K/Akt.
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