title: RFamide peptides 43RFa and 26RFa both promote survival of pancreatic β-cells and human pancreatic islets but exert opposite effects on insulin secretion.
abstract: RFamide peptides 43RFa and 26RFa have been shown to promote food intake and to exert different peripheral actions through G-protein-coupled receptor 103 (GPR103) binding. Moreover, 26RFa was found to inhibit pancreatic insulin secretion, whereas the role of 43RFa on β-cell function is unknown, as well as the effects of both peptides on β-cell survival. Herein, we investigated the effects of 43RFa and 26RFa on survival and apoptosis of pancreatic β-cells and human pancreatic islets. In addition, we explored the role of these peptides on insulin secretion and the underlying signaling mechanisms. Our results show that in INS-1E β-cells and human pancreatic islets both 43RFa and 26RFa prevented cell death and apoptosis induced by serum starvation, cytokine synergism, and glucolipotoxicity, through phosphatidylinositol 3-kinase/Akt- and extracellular signal-related kinase 1/2-mediated signaling. Moreover, 43RFa promoted, whereas 26RFa inhibited, glucose- and exendin-4-induced insulin secretion, through Gαs and Gαi/o proteins, respectively. Inhibition of GPR103 expression by small interfering RNA blocked 43RFa insulinotropic effect, but not the insulinostatic action of 26RFa. Finally, 43RFa, but not 26RFa, induced cAMP increase and glucose uptake. In conclusion, because of their survival effects along with the effects on insulin secretion, these findings suggest potential for 43RFa and 26RFa as therapeutic targets in the treatment of diabetes.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy riccarda.granata@unito.it.
authors.forename: Riccarda
authors.initials: R
authors.lastname: Granata
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Settanni
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Trovato
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Gallo
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Iacopo
authors.initials: I
authors.lastname: Gesmundo
authors.affiliation: Diabetes Research Institute, Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Nano
authors.affiliation: Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Gallo
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Bergandi
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Volante
authors.affiliation: Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alloatti
authors.affiliation: Diabetes Research Institute, Division of Immunology, Transplantation, and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Piemonti
authors.affiliation: Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, International Associated Laboratory Samuel de Champlain, Institute for Research and Innovation in Biomedicine, INSERM U-982, University of Rouen, Rouen, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Leprince
authors.affiliation: Department of Oncology, University of Torino, Torino, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Papotti
authors.affiliation: Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, International Associated Laboratory Samuel de Champlain, Institute for Research and Innovation in Biomedicine, INSERM U-982, University of Rouen, Rouen, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.affiliation: Faculty of Pharmacy, University of Montréal, Montréal, Québec, Canada.
authors.forename: Huy
authors.initials: H
authors.lastname: Ong
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Ghigo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000187:drug effects* / Q000502:physiology; D009479:Neuropeptides / Q000494:pharmacology*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: C575415:43RFa peptide, human; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; D010455:Peptides; C511787:QRFP peptide; C476582:QRFPR protein, human; C416987:RFamide peptide; D043562:Receptors, G-Protein-Coupled; C480638:prepro-26RFa protein, human