Does glucocorticoid dysregulation contribute to the link between cigarette smoking and insulin resistance?

In a recent issue of the Journal, Drs. Reaven and Tsao (1) discussed the association between cigarette smoking and insulin resistance, endothelial dysfunction, and dyslipidemia. They assert that insulin resistance may be a key mechanism by which smoking increases the risk of atherosclerotic cardiovascular disease. We agree with this assertion and suggest that elevated glucocorticoid tone may be an important link between cigarette smoking and insulin resistance. Cigarette smokers may have higher serum cortisol levels than nonsmokers of similar age and body mass index (BMI) (2). Furthermore, elevated afternoon cortisol levels appear to fall after smoking cessation (3). Although the mechanisms for altered glucocorticoid homeostasis in smokers remains to be defined, it is well known that long-term glucocorticoid exposure causes visceral obesity and carbohydrate insulin resistance, and it is also likely that interindividual variation in glucocorticoid homeostasis contributes to insulin resistance in the general population (4). Thus, it is plausible that chronically dysregulated glucocorticoid homeostasis in smokers may have adverse effects on glucose metabolism and body fat distribution. Visceral obesity—even when BMI is normal or low—is associated with insulin resistance and increased cardiovascular risk, and cigarette smokers may have a two-fold greater risk of developing this anthropometric phenotype compared with nonsmokers (5). This observation provides further circumstantial evidence that altered glucocorticoid homeostasis in smokers might have chronic consequences. In summary, the link between smoking and insulin resistance may be at least partly explained by elevated activity of the stress hormone cortisol.