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Although cigarette smoking is associated with insulin resistance and an increased risk for type 2 diabetes (1), few studies have examined the metabolic and molecular effects of smoking cessation in humans. Epidemiological data from the Atherosclerosis Risk in Communities study in middle-aged men and women offer several insights into the relationship between smoking cessation and diabetes. This study suggests that individuals who quit smoking are at increased risk of type 2 diabetes and that this risk is highest in the first 2 years after smoking cessation, but that risk declines after this point until no excess risk is observed at 12 years after cessation. The increased risk of type 2 diabetes associated with smoking cessation seems to be partially mediated by weight gain (2,3). In this issue of Diabetes, Bergman et al. (4) examined the metabolic and molecular effects of smoking cessation (for 1-2 weeks) in young, lean, otherwise healthy college students, a population that is increasingly vulnerable to the effects of both cigarette smoking and second-hand smoke exposure. Their results suggest that skeletal muscle insulin resistance in smokers is associated with increased mammalian target of rapamycin (mTOR)/p70S6 ? activity and insulin receptor substrate- 1 (IRS-1) Ser636 phosphorylation by nicotine, and these effects are reversible with smoking cessation.
Cigarette smoking increases energy expenditure (Fig. 1), and this effect may be mediated in part by the sympathetic nervous system (5). In addition, smoking enhances lipid mobilization. Hellerstein et al. (6) demonstrated that cigarette smoking acutely increased free fatty acid (FFA) and glycerol fluxes as well as circulating FFA concentrations due to nicotine-induced lipolysis. Cigarette smoking increased delivery of FFA to the liver, increased hepatic reesterification of FFA, and enhanced VLDL secretion, thereby promoting the atherogenic effects of smoking. There were no acute effects of smoking on de novo lipogenesis, whole body fat oxidation, adipocyte reesterification of FFA, or basal hepatic glucose production. Finally, cessation of smoking for a period of only 1 week (while on an isocaloric diet) was not associated with a rebound reduction in fat mobilization, suggesting the absence of a metabolic predisposition to gain weight, assuming there is no increase in caloric intake. However, chronic nicotine withdrawal increases appetite and food intake. Nicotine directly activates the brain melanocortin system in rodents via hypothalamic...