Inflammation and Insulin Resistance in RARheumatoid arthritis (RA), affects approximately 1% of the population and is associated with anincreased prevalence of ischemic heart disease. We have shown that the prevalence of coronaryartery atherosclerosis is increased markedly in patients with RA, but the underlying mechanismsare not known. In preliminary studies we found that insulin concentrations are more than 2-foldhigher in patients with RA than controls and are correlated with inflammatory markers such as IL6,TNF and CRP, and with coronary atherosclerosis. Thus, related processes, inflammation andhyperinsulinemia, contribute mechanistically to increased cardiovascular morbidity in RA. Therelationship between hyperinsulinemia and inflammation is bi-directional - inflammation facilitatesinsulin resistance, and insulin resistance promotes chronic inflammation. Thiazolidinediones,selective PPARy agonists, are insulin sensitizers even in individuals without diabetes and are apowerful tool to understand the mechanisms underlying the realtionship between inflammation andinsulin resistance. Thiazolidinediones, not only improve insulin sensitivity, but also decreaseinflammation, including arthritis in animal models. Thus, in a proof-of-concept translational study,we will randomize patients with RA to receive pioglitazone or placebo for 6 months to test thehypotheses that treatment with a PPARy agonist will decrease inflammation (Specific Aim 1),improve insulin sensitivity (Specific Aim 2) and improve augmentation index (Specific Aim 3) inpatients with RA. The proposed studies will provide mechanistic information regarding therelationship between inflammation and hyperinsulinemia, and will identify novel strategies forpotentially reversing or preventing the long term damage to joints and the vasculature in RA, andperhaps other inflammatory diseases.
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