Effects of Pioglitazone on Igh-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 igh-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 agonists and this class of drugs have demonstrated several other potential benefits, in addition to their effects on glucose homeostasis. PPAR-γ agonists can improve diabetic dyslipidemia, in which PIO increases HDL cholesterol and lowers triglycerides. Evidence demonstrating that TZDs reduce carotid arterial intima-media thickness provide evidence of an anti-atherogenic effect of PPAR-γ activators and might imply benefits beyond glycemic control for patients treated with this class of drugs. 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.

The investigators hypothesize that increased levels of HDL resulting from PIO therapy will affect particle size, density distribution and the lipid and lipoprotein composition of HDL and that such changes may alter the activity of several key steps involved in reverse cholesterol transport, namely the ability to promote cellular cholesterol efflux, cholesterol esterification by LCAT and transport of esterified cholesterol from HDL to the apoB containing lipoproteins.