Effects of Pioglitazone on High-density Lipoprotein (HDL) Function in Persons With Diabetes

Metabolic defects contributing to the development of type 2 diabetes (T2D) are relative insulin insufficiency and insulin resistance that are associated with a cluster of abnormalities that increase the risk for cardiovascular disease including dyslipidemia, inflammation, hemodynamic changes and endothelial dysfunction. The dyslipidemia associated with T2D is characterized by elevated triglycerides and decreased high-density lipoprotein-cholesterol (HDL). The ability of the insulin sensitizing agent pioglitazone (ACTOS®) , to improve hyperglycemia in subjects with T2D is now well established. Pioglitazone functions as a PPAR-γ (peroxisome proliferator-activated receptor gamma) agonists and this class of drugs have demonstrated several other potential benefits, beyond glucose homeostasis. Specifically pioglitazone can improve diabetic dyslipidemia by increasing HDL cholesterol and lowing triglycerides. A potential beneficial effect on reverse cholesterol transport may be mediated by the increased HDL levels. This proposal aims to examine the effect of PPAR-γ activation by PIO on various aspects of reverse cholesterol transport by testing the hypothesis that PIO treatment affects key steps in the reverse cholesterol transport pathway either directly, through induction of protein expression, or indirectly, by altering HDL structure and composition leading to increase cholesterol flux through this pathway.