title: Ghrelin's Effects on Proinflammatory Cytokine Mediated Apoptosis and Their Impact on β-Cell Functionality.
abstract: Ghrelin is a peptidic hormone, which stimulates cell proliferation and inhibits apoptosis in several tissues, including pancreas. In preclinical stage of type 1 diabetes, proinflammatory cytokines generate a destructive environment for β-cells known as insulitis, which results in loss of β-cell mass and impaired insulin secretion, leading to diabetes. Our aim was to demonstrate that ghrelin could preserve β-cell viability, turnover rate, and insulin secretion acting as a counter balance of cytokines. In the present work we reproduced proinflammatory milieu found in insulitis stage by treating murine cell line INS-1E and rat islets with a cytokine cocktail including IL-1β, IFNγ, and TNFα and/or ghrelin. Several proteins involved in survival pathways (ERK 1/2 and Akt/PKB) and apoptosis (caspases and Bcl-2 protein family and endoplasmic reticulum stress markers) as well as insulin secretion were analyzed. Our results show that ghrelin alone has no remarkable effects on β-cells in basal conditions, but interestingly it activates cell survival pathways, downregulates apoptotic mediators and endoplasmic reticulum stress, and restores insulin secretion in response to glucose when beta-cells are cytokine-exposed. These data suggest a potential role of ghrelin in preventing or slowing down the transition from a preclinical to clinically established diabetes by ameliorating the effects of insulitis on β-cells.
authors.affiliation: Research Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Diaz-Ganete
authors.affiliation: Research Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain ; Department of Endocrinology and Nutrition, Jerez de la Frontera General Hospital, 11407 Jerez de la Frontera, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: Baena-Nieto
authors.affiliation: Research Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain ; Andalusian Cellular Reprogramming Laboratory, 41092 Sevilla, Spain.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Lomas-Romero
authors.affiliation: Research Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain ; Genetics and Molecular Biology Research Institute, University of Valladolid-CSIC, 47003 Valladolid, Spain.
authors.forename: Jose Francisco
authors.initials: JF
authors.lastname: Lopez-Acosta
authors.affiliation: Genetics and Molecular Biology Research Institute, University of Valladolid-CSIC, 47003 Valladolid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Cozar-Castellano
authors.affiliation: Research Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain ; Salus Infirmorum Faculty of Nursing, Cadiz University, 11001 Cadiz, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Medina
authors.affiliation: Research Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain ; Salus Infirmorum Faculty of Nursing, Cadiz University, 11001 Cadiz, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Segundo
authors.affiliation: Research Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain ; Department of Maternal and Pediatric Medicine and Radiology, Pediatrics Unit, Puerta del Mar University Hospital, 11009 Cadiz, Spain.
authors.forename: Alfonso M
authors.initials: AM
authors.lastname: Lechuga-Sancho