title: Exendin-4 protects murine MIN6 pancreatic β-cells from interleukin-1β-induced apoptosis via the NF-κB pathway.
abstract: BACKGROUND
  Glucagon-like peptide-1 (GLP-1) and its potent analog, exendin-4, are well known to inhibit β- cell apoptosis and promote β-cell proliferation. Meanwhile, cytokines, such as interleukin-1β (IL-1β), stimulate inducible nitric oxide synthase (iNOS) expression and nitric oxide overproduction leading to β-cell damage. However, the protective mechanisms of GLP-1 in β-cells exposed to cytokines have not been fully elucidated.
  
  
  OBJECTIVE
  In this study, the protective effects of exendin-4 on IL-1β-induced apoptosis were investigated in murine MIN6 pancreatic β-cells. The role of nuclear factor-κB (NF-κB) signaling in this process was also explored.
  
  
  METHODS
  The effects of exendin-4 pre-treatment on IL-1β-induced apoptosis were investigated by Hoechst/PI and Annexin V/PI staining. Levels of iNOS and NF-κB proteins were investigated by Western blotting and cytoplasmic nitrite levels were determined using Griess reagent.
  
  
  RESULTS
  IL-1β treatment (range, 5-40 ng/ml) for 24 h was positively correlated with nitrite production (R2=0.9668, p<0.01), a significant increase in the percentage of apoptotic cells (p<0.01) and a concomitant dose-dependent increase in cytoplasmic levels of iNOS and NF-κB p65 activation. N-acetyl- L-cysteine (NAC), NG-nitro-L-arginine methyl ester (L-NAME) and pyrrolidine dithiocarbamate (PDTC), partially rescued apoptotic β-cells, suggesting involvement of NF-κB-iNOS-nitrite in this process. Exendin-4 (100 nM) treatment significantly decreased IL-1β-induced apoptosis (p<0.01), downregulated NF-κB activation and subsequently decreased iNOS and nitrite levels in IL-1β-induced β-cells (p<0.001), in a similar manner to L-NAME, PDTC and NAC.
  
  
  CONCLUSIONS
  These results suggest that exendin-4 protects against IL-1β- induced apoptosis in β-cells via downregulation of the NF- κB-iNOS-nitrite pathway.
authors.affiliation: Department of Endocrinology, Fujian Institute of Endocrinology, Union Hospital of Fujian Medical University, 29 Xinquan Road, Fuzhou, Fujian 350001, People's Republic of China.
authors.forename: X H
authors.initials: XH
authors.lastname: Liu
authors.forename: Y P
authors.initials: YP
authors.lastname: Wang
authors.forename: L X
authors.initials: LX
authors.lastname: Wang
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: X Y
authors.initials: XY
authors.lastname: Liu
authors.forename: L B
authors.initials: LB
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D007004:Hypoglycemic Agents; D053583:Interleukin-1beta; D016328:NF-kappa B; D010455:Peptides; D014688:Venoms; D009569:Nitric Oxide; D000077270:Exenatide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse