In our prospective study of 100,526 women followed for 24 years, we found that exposure to passive smoke and active smoking were independently associated with the risk of developing type 2 diabetes. The association appeared dose dependent and remained significant after carefully controlling for multiple relevant lifestyle and dietary factors. After quitting, the risk of diabetes decreased gradually but still was significantly elevated 20 years later.
Several mechanisms may be involved in the increased risk of diabetes among smokers. First, cigarette smoking has been related to various systemic effects, including oxidative stress, systemic inflammation, and endothelial dysfunction, as reviewed by Yanbaeva et al. (12
). Each of these effects has been strongly implicated in insulin resistance (13
) and diabetes risk (10
). Second, even though smokers tend to have a lower mean BMI compared with nonsmokers, they have a more metabolically adverse fat distribution profile, with higher central adiposity (16
). Finally, smoking could directly damage β-cell function (17
) or induce chronic pancreatic inflammation (18
). Those studies provide biological plausibility for a causal relation between smoking and diabetes.
There is fairly strong evidence supporting active smoking as a risk factor for type 2 diabetes. A recent meta-analysis (3
) involving 25 prospective cohort studies reported a pooled adjusted RR of 1.44 (95% CI 1.31–1.58) for active smoking. However, our analysis, as well as previous studies (4
), demonstrate that a large proportion of nonactive smokers (the reference group used in the recent meta-analysis [3
]) may be exposed to passive smoke and that these participants are at increased risk of diabetes compared with individuals without any active or passive smoke exposure (5
). Thus, the pooled RR of 1.44 reported in the meta-analysis may be a systematic underestimate of the true magnitude of the association, which is supported by our secondary analysis using all nonsmokers as the reference group (1.50 [1.35–1.66]). Furthermore, many of the studies included in the meta-analysis did not control for certain important lifestyle and dietary variables, such as alcohol intake and caffeine intake, which we and others have found to be important negative confounders in the association between smoking and risk of diabetes (20
). The inability in the meta-analysis to account for these variables also would tend to produce an underestimate of the true association. That meta-analysis did not include main results from our cohort that showed a link between smoking and diabetes risk; these data, which were published nearly two decades ago (22
), demonstrated an RR of type 2 diabetes among women who smoked ≥25 cigarettes per day compared with nonactive smokers of 1.49 (1.19–1.87) (22
). Although women from that study also are included in the present analysis, we have expanded on the approach by taking passive smoke exposure into account, rigorously analyzing duration since quitting, adjusting for additional confounders, and also have 16 additional years of follow-up.
Several longitudinal studies investigated the association of smoking cessation on the risk of diabetes. Data from the Cancer Prevention Study suggested that quitting smoking reduced the rate of diabetes to that of nonsmokers after 5 years in women and after 10 years in men (23
). Updated information of smoking status, lifestyle, and diet were not available in that study. Another study among middle-aged British men (24
) indicated that starting from 5 years after smoking cessation, the risk of type 2 diabetes started to decrease compared with current smokers; however, the risk of diabetes was not equivalent to the risk among nonsmokers until 20 years after quitting (24
). In our study, the risk of diabetes still was elevated 20 years after quitting, with an adjusted RR of 1.18 (95% CI 1.01–1.38). The same reasons for why the association between active smoking and diabetes were stronger in our analysis compared with the previous meta-analysis also may explain why a longer duration of quitting was required for risk equalization in our study compared with these previous two studies. Specifically, these two previous studies did not exclude passive smokers from the reference group and did not have information on all relevant confounders.
Our study has strengths and limitations that deserve mention. A major strength of this study, aside from its prospective nature and high follow-up rate, is the ability to control for various potential confounders and other known risk factors of diabetes. Confounding by time-varying covariates, especially lifestyle and dietary variables, is minimized by updating covariates every 2–4 years. Our study has limitations as well. For example, diabetes was self-reported. However, all of the participants were registered nurses, and self-reported diabetes was verified by a validated supplementary questionnaire (11
). The possibility for residual confounding by unmeasured material and cultural factors, especially for the association between passive smoking and risk of diabetes, cannot be fully eliminated. In addition, our population was almost entirely white and exclusively female; thus, our results may not be generalizable to other populations. However, the relative homogeneity of the cohort in educational attainment and socioeconomic status actually may serve to enhance the internal validity of this study.
Another important limitation was the way in which we ascertained passive smoke exposure. First, we relied on self-reports of passive smoke exposure. Self-reports of exposure to passive smoke are only modestly correlated with biomarkers of tobacco-smoke exposure, such as serum cotinine (19
). Part of the reason is the ubiquitous nature of passive smoke. A study of 663 subjects who never used tobacco and former tobacco users revealed that cotinine was found in the urine of 91% of participants, whereas only 76% reported exposure to passive smoke (19
). Second, our assessment of passive smoke exposure was ascertained only at baseline in 1982, and it is likely that exposure to passive smoke changed over time because of individual factors (e.g., retirement) or societal factors (e.g., national interventions to reduce smoking). These two limitations would tend to result in misclassification, such that those women reporting little or no exposure in 1982 actually may have had important levels of exposure, whereas those reporting heavy exposure in 1982 may have had less exposure in the later years of follow-up. This type of misclassification would tend to produce weaker RR estimates than would hypothetically be observed in an ideal study. Therefore, we may have actually underestimated the true magnitude of the association between exposure to passive smoke and diabetes.
In conclusion, our prospective analysis suggests that smoking is strongly and independently associated with the risk of incident type 2 diabetes in a dose-dependent manner. Among former active smokers, the increased risk of diabetes persisted for 20 years after smoking cessation. Previous studies may have underestimated the magnitude and duration of the increased risk of diabetes associated with smoking.