The role of reactive oxygen species in insulin resistance

Insulin resistance and type II diabetes mellitus are major public health issues in the U.S.; more specifically insulin resistance is strongly correlated with obesity. Multiple factors influence insulin resistance such as hyperglycemic conditions and increased levels of reactive oxygen species (ROS). As oxygen radicals accumulate in adipocytes from increased glucose oxidation, they interfere with insulin signaling and affect glucose uptake. To determine if insulin sensitivity can be prolonged with the aid of antioxidants, adipocytes were maintained in a high glucose medium supplemented with antioxidants ascorbic acid or &alpha-tocopherol and then tested for insulin sensitivity. Our studies reveal that ROS levels fluctuate in insulin resistant adipocytes (Day 11-21). We show for the first time that there is a decrease in ROS levels at Day 13, which then significantly increase at Day 15 and this trend continues every other day till Day 21. At Day 10 and 15 the ROS levels are high, but adipocytes have high GLUT4 expression at Day 10 and decreased expression on Day 15. By Day 15 there is increased phosphorylation of AKT but no change in IRS-1 phosphorylation. The levels of ROS were significantly decreased with the application of antioxidants. With decreased ROS levels there was overall increased phosphorylation of IRS-1 and AKT. The lipid content and distribution was not affected by ROS levels. In conclusion, the development of insulin resistance is effected by ROS, however the data indicates that there is a mechanism independent of AKT, or a target downstream of AKT that is affected and leading to the development of insulin resistance. ROS levels also regulate the expression of GLUT4 and thus GLUT4-mediated glucose uptake resulting in resistance to insulin signaling. Insulin resistance is affected by ROS levels differently if it is added exogenously, or if it is amassed endogenously. Identification of factors that interfere with insulin signaling and thus type II diabetes, like ROS levels, can lead to the development of possible therapeutic treatments