The prevalence of Type 2 Diabetes Mellitus (T2DM), a serious and costly disease, has increased dramatically in the past 2 decades. Current therapies for diabetes are expensive and are unable to prevent the long-term complications of the disease. New strategies to prevent or delay the onset of type 2 diabetes would prevent or delay the onset of diabetic complications, and therefore decrease patient suffering and save the health care system billions of dollars. We have recently developed a new rat model of type 2 diabetes that exhibits both adult-onset obesity induced insulin resistance and an impairment of pancreatic Beta-cell function. This model is more relevant to type-2 diabetes in humans and therefore an appropriate animal model for testing new approaches for diabetes prevention. We propose to determine the efficacy of several widely used nutritional supplements known to activate PPARs and/or target lipid dysregulation, inflammation, and oxidative stress to prevent or delay the onset of T2DM in this rat model. We will pursue the following specific aims: Specific Aim 1: We hypothesize that supplementation with omega 3 fatty acid eicosapentaenoic acid (EPA) will activate PPARalpha, gamma and delta and prevent or delay the onset of T2DM. We will also determine whether purified EPA will attenuate the development of diabetes more effectively than fish oil supplements. Specific Aim 2: We hypothesize that supplementation with a-lipoic acid will reduce oxidative stress, thereby preventing or delaying onset of T2DM. We will also investigate whether a-lipoic acid in combination with the marine oil PPAR activators (EPA & DMA) will be more effective than a-lipoic acid alone in preventing diabetes. Further studies to investigate the mechanism(s) of action of the supplements or the supplement combinations that are effective in preventing/delaying diabetes onset of diabetes in this model are proposed. [unreadable] [unreadable]