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This Article Full Text Full Text (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 Google Scholar Articles by Blandino-Rosano, M Articles by Aguilar-Diosdado, M PubMed PubMed Citation Articles by Blandino-Rosano, M Articles by Aguilar-Diosdado, M

Investigation Unit and Endocrinology and Nutrition Service, Puerta del Mar Hospital, Ana de Viya, 21, Cadiz 11009, Spain

(Correspondence should be addressed to C Segundo; Email: carmen.segundo.exts{at}juntadeandalucia.es; M Aguilar-Diosdado; Email: manuel.aguilar.sspa{at}juntadeandalucia.es)

^* *C Segundo and M Aguilar-Diosdado have participated equally in the study and the preparation of this manuscript

Pancreatic β-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of β-cell mass loss by pro-inflammatory cytokine-induced apoptosis, influences of a pro-inflammatory environment on β-cell regenerative response have been poorly studied. In this study, we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic β 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 interleukin (IL)-1β, interferon (IFN)-, and tumour necrosis factor- (TNF-) were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation, the signaling pathway involved in β-cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased β-cell proliferation threefold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and β-cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. These data suggest a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic β cells as well as to delay the development of overt diabetes.