Anti-proliferative effect of pro-inflammatory cytokines in cultured β cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide -1

Pancreatic b-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 b-cell mass loss by pro-inflammatory cytokineinduced apoptosis, influences of a pro-inflammatory environment on b-cell regenerative response have been poorly studied.Inthisstudy,weassesstheanti-proliferativeeffectofpro-inflammatorycytokinesandglucoseconcentrationonrat pancreatic b 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 0 -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)-1b, interferon (IFN)-g, and tumour necrosis factor-a (TNF-a) 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 b-cell replication. GLP-1 completely reversed the cytokine-inducedinhibitionofERKphosphorylationandincreasedb-cellproliferationthreefoldincytokine-treatedcultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and b-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