Decreased Sirt3 contributes to cyclic production of reactive oxygen species and islet beta-cell apoptosis in high glucose conditions

Background Reactive oxygen species (ROS) plays a vital role in the apoptosis of islet beta-cells in type 2 diabetes mellitus (T2DM). Sirt3 (Sirtuin 3, a deacetylase) and FoxO1 (a transcription factor) might be involved in ROS production. This study was to investigate mechanism of ROS production and beta-cell apoptosis in T2DM. Methods Oxidative stress and apoptosis in islets of db/db mice and high glucose cultured beta-cells were observed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay and western blotting. Then, H2O2 was used to ascertain the effect of ROS on the expression of Sirt3. Meanwhile, FoxO1, antioxidant enzymes - catalase (CAT) and manganese superoxide dismutase (MnSOD) and beta-cell apoptosis were also determined by western blotting. Finally, Sirt3 was knocked down to evaluate the effect on oxidative stress and apoptosis of beta-cells. Results Under high glucose environment, enhanced ROS made a decrease of Sirt3 expression, which increased acetylation of FoxO1, thus reduced the expression of its target proteins -MnSOD and CAT, and further significantly increased ROS levels. Increased ROS finally led to the apoptosis of beta-cells. Conclusion Down-regulation of Sirt3 plays an important role in the cyclic production of ROS and beta-cell apoptosis. Targeting Sirt3 may be favorable for the treatment of T2DM.