Role of Reactive Oxygen Species in HIV‐1 Protease Inhibitors‐Induced Decrease in Insulin Release by INS‐1 Cells : Protection by Antioxidants

The inclusion of HIV‐1 protease inhibitors (PIs) in highly active anti‐retroviral therapy (HAART) has significantly improved the prognosis of HIV‐1+ patients. However, long term use of PIs has been associated with insulin resistance, cardiovascular dysfunction and lipodystrophy. Recent findings suggest that exposure to PIs may decrease insulin secretion from rat pancreatic β cells (INS‐1) but the mechanism linked to this deleterious effect of PIs is not delineated. We hypothesize that HIV‐1 PIs dysregulate glucose induced insulin secretion by β‐cells via increased oxidative stress. We have demonstrated that HIV‐1 PI, nelfinavir (5–10μM) significantly decreased glucose induced insulin secretion in INS‐1cells after 24 hr. This decrease preceded a siginificant increase in ROS levels in INS‐1 cells under identical conditions. Superoxide dismutase levels were also decreased by 40%. Simultaneous exposure of INS‐1 cells to thymoquinone (100nM), an active ingredient of black seed oil, inhibited the production of ROS. These findings suggest that thymoquinone cotreatment may provide protection from the toxicity of PIs. In conclusion, this study implicates ROS as a possible mechanism for HIV‐1 PI induced deleterious effects in pancreatic β‐cells, which may be ameliorated by the use of potent antioxidants.