? ? This is a proposed supplemental study to the existing Program Project Grant (PPG) investigating the cardiovascular toxicity of environmental aldehydes. Concordant with the overall theme of the PPG to elucidate the role of cardiovascular (CV) oxidative stress in environmentally-induced oxidative injury, this project will examine the effects of ambient air particles on insulin resistance. While multiple studies suggest that diabetes increases susceptibility to PM2.5-induced CV events, emerging evidence supports also the existence of the reciprocal relationship, i.e., exposure to PM2.5 may increase the risk of developing diabetes. Developing on the on going PPG studies showing that exposure to acrolein induces dyslipidemia consistent with insulin resistance and drawing from previous epidemiological and experimental studies, this project will test the hypothesis that exposure to concentrated ambient PM2.5 (CAP) acutely triggers a state of insulin resistance. The investigators propose that CAP-induced reduction in insulin sensitivity is mediated in part by oxidative stress, increased generation of oxidation-derived aldehydes, and mild dyslipidemia. Accordingly, they will measure the effect of CAP on insulin sensitivity in 50 health adults by the frequently sampled intravenous glucose tolerance test in a series of randomized, double-blind, cross-over exposures to filtered air versus CAP ? anti-oxidant pre-treatment. To probe underlying mechanisms, they will determine the nature and the extent of oxidative stress using sensitive and unique assays developed by the PPG investigators and will elucidate specific features of oxidative injury associated with changes in vascular function and sympathetic tone. In addition, the investigators will characterize CAP and delineate, in particular, the contribution of environmental aldehydes to changes in vascular reactivity and insulin resistance. Collaboration with the PPG will facilitate exchanges of intellectual and material resources by linking laboratory science to clinical research. The investigators expect that the bioanalytical tools, and reagents, and the range of animal data will provide continuous support and orientation to the clinical study, which in turn will provide input and direction for clinically meaningful evaluation of laboratory end points. This arrangement will enhance the scope and the breath of the on going PPG and help in critically assessing how air pollution causes insulin resistance and thereby contributes to the epidemic of diabetes currently unfolding within the industrialized world. ? ? ? ?
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