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

Laboratory of Molecular and Cellular Endocrinology (R.G., F.S., L.T., S.D., M.A.), Division of Endocrinology and Metabolism (R.G., F.S., L.T., S.D., M.A., E.G.), and Departments of Internal Medicine (R.G., F.S., L.T., S.D., M.A., E.G., L.B.), Anatomy, Pharmacology, and Forensic Medicine (F.C., M.M., C.G., G.M.), and Clinical and Biological Sciences and San Luigi Hospital (M.P.), University of Turin, 10126 Turin, Italy; Department of Medicine (R.N., F.B.), Transplant Unit, Scientific Institute San Raffaele, Vita-Salute University, 20132 Milan, Italy; and Department of Internal Medicine (J.I.), Sahlgrenska Academy, University of Göteborg, SE-40530 Göteborg, Sweden

Address all correspondence and requests for reprints to: Riccarda Granata, Ph.D., Laboratory of Molecular and Cellular Endocrinology, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Corso Dogliotti 14, 10126 Turin, Italy. E-mail: riccarda.granata{at}unito.it.

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

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