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Bioscience Reports (2010) Immediate Publication, doi:10.1042/BSR20090138
The effects of pharmacologic inhibition of NADPH oxidase or iNOS on pro-inflammatory cytokine, palmitic acid or H2O2 -induced mouse islet or clonal pancreatic beta cell dysfunction
Marta Michalska, Gabriele Wolf, Reinhard Walther and Philip Newsholme
School of Biomolecular and Biomedical Science, UCD Dublin, Dublin 4, Republic of Ireland. philip.newsholme@ucd.ie
Various pancreatic beta cell stressors including cytokines and saturated fatty acids are known to induce oxidative stress which results in metabolic disturbances and a reduction in insulin secretion. However, the key mechanisms underlying dysfunction are unknown. We have investigated the effects of prolonged exposure (24 hr) to pro-inflammatory cytokines, H2O2 or palmitic acid, on beta cell insulin secretion, ATP, the NADPH oxidase component p47phox and iNOS levels using primary mouse islets or clonal rat BRIN-BD11 beta cells. Addition of a pro-inflammatory cytokine mixture (IL-1β, TNF-α and IFN-γ) or H2O2 (at sub-lethal concentrations) inhibited chronic (24hr) levels of insulin release by at least 50% (from islets and BRIN-BD11 cells), while addition of the saturated fatty acid palmitate inhibited acute (20min) stimulated levels of insulin release from mouse islets. H2O2 decreased ATP levels in the cell line, but elevated p47phox and iNOS levels as did cytokine addition. Similar effects were observed in mouse islets with respect to elevation of p47phox and iNOS levels. Addition of the antioxidants superoxide dismutase, catalase and N-acetylcysteine attenuated H2O2 or the saturated fatty acid palmitate dependent effects but not cytokine induced dysfunction. However specific chemical inhibitors of NADPH oxidase and/or iNOS appear to significantly attenuate the effects of cytokines, H2O2 or fatty acids in islets. While pro-inflammatory cytokines are known to increase p47phox and iNOS levels in beta cells, we now report that H2O2 can increase levels of the latter two proteins suggesting a key role for positive-feedback redox sensitive regulation of beta cell dysfunction.
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