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Insulin resistance and endothelial dysfunction in smokers: effects of vitamin C. Am J Physiol Heart Circ Physiol 279: H1172-H1178, 2000.--Cigarette smoking impairs endothelial function and is one of the major risk factors for atherosclerosis and coronary heart disease. Insulin resistance is associated with major risk factors for atherosclerosis. We examined the effects of vitamin C on insulin sensitivity and endothelial function by measuring steady-state plasma glucose (SSPG) and flow-mediated dilation (FMD) of the brachial artery. We studied 16 current smokers with normal glucose tolerance, 15 nonsmokers with impaired glucose tolerance (IGT), and 17 nonsmokers with normal glucose tolerance as controls. Both SSPG and FMD were blunted in smokers and nonsmokers with IGT compared with controls. In smokers, vitamin C decreased SSPG (P [is less than] 0.01 by ANOVA) with decreasing plasma thiobarbituric acid-reactive substances (TBARS) (P [is less than] 0.05 by ANOVA) and improved FMD (P [is less than] 0.05 by ANOVA). Furthermore, vitamin C improved both SSPG (P [is less than] 0.005 by ANOVA) and FMD (P [is less than] 0.05 by ANOVA) in nonsmokers with IGT. SSPG, FMD, or TBARS in controls did not change after vitamin C infusion. There was a significant correlation between SSPG and FMD both in smokers and nonsmokers with IGT, whereas no correlation was observed in controls. In conclusion, both insulin sensitivity and endothelial function were impaired in smokers and nonsmokers with IGT and were improved by vitamin C. Thus increased reactive oxygen species play an important role in the pathogenesis of insulin resistance as well as endothelial dysfunction in smokers and nonsmokers with IGT. oxidative stress; cigarette smoking; insulin sensitivity; endothelial function