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This Article Accepted manuscript (PDF) All Versions of this Article: JME-07-0154v1 41/1/35    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Blandino-Rosano, M. Articles by Aguilar-Diosdado, M. Search for Related Content PubMed PubMed Citation Articles by Blandino-Rosano, M. Articles by Aguilar-Diosdado, M.

M Blandino-Rosano, Unidad de Investigacion, Hospital U. Puerta del Mar, Cadiz, Spain
G Perez-Arana, Unidad de Investigacion, Hospital U. Puerta del Mar, Cadiz, Spain
J Mellado-Gil, Unidad de Investigacion, Hospital U. Puerta del Mar, Cadiz, Spain
C Segundo, Hospital U. Puerta del Mar, Cadiz, Spain
M Aguilar-Diosdado, Servicio de Endocrinologia y Nutricion, Hospital U. Puerta del Mar, Cádiz, Spain

Correspondence: Carmen Segundo, Email: carmen.segundo.exts{at}juntadeandalucia.es

Abstract

Pancreatic beta cell homeostasis is a balance between programmed cell death (apoptosis) and of regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of beta cell mass loss by pro-inflammatory cytokine-induced apoptosis, influences of a pro-inflammatory environment in beta cell regenerative response has been poorly studied. In this study we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic beta cells and the potential protective role of glucagon-like peptide (GLP-1). Apoptotic and proliferating islet cells were stained using the DeadEnd Fluorimetric TUNEL System and 5-Bromo-2’-Deoxyuridine label, respectively, in the presence-absence of varying concentrations of glucose, pro-inflammatory cytokines and GLP-1. The potential signaling pathways involved were evaluated by western blot. Considerable anti-proliferative effects of pro-inflammatory cytokines IL-1β, IFN- and TNF- were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by inhibition of ERK 1/2 activation; the signaling pathway involved in beta cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased beta cell proliferation 3-fold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and beta cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. This suggests a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic beta cells as well as to delay the development of overt diabetes.