Several important physiological changes occur before overt clinical onset of DM (). The insulin resistance and hyperinsulinemia characteristic of pre-diabetes may affect colon cancer risk before DM diagnosis, but epidemiological data regarding cancer incidence in the pre-diabetic state remain limited. In 2007, Giovannucci and Michaud 
hypothesized that hyperinsulinemia is the critical factor responsible for increased colon cancer risk in DM, citing evidence from animal modeling and epidemiological studies 
. However, this is the first report to comprehensively examine the temporal relationship between DM and colon cancer, including the time period before clinical DM onset, and the evidence presented here suggests that the greatest increase in the risk of colon cancer occurs before DM onset and is essentially limited to men.
Decreased NNEH over time to DM onset in men suggests a cumulative oncogenic effect with progression through the pre-diabetes phase, whereby fewer men need to be exposed to the pre-DM milieu over time for each additional case of colon cancer. No such difference was observed after clinical DM onset. Together, these findings support the notion that hyperinsulinemia and factors that cause hyperinsulinemia, such as obesity, physical inactivity, and an unbalanced diet, may result in increased oncogenic potential in the colon 
. Lack of such an association in women suggests that gender differences in colon cancer risk are discernible early in the diabetes trajectory.
Several meta-analyses have been published that report a similar increase in risk of colon cancer in men or women with diabetes or metabolic syndrome 
. However, there is also significant evidence that points to increase risk in men. In a 2009 systematic review and meta-analysis, Nguyen et al. 
observed a predilection of colorectal adenomas for men (RR
1.83, 95% CI 1.69–1.97). Further, a meta-analysis of screening colonoscopy studies reported a lower adenoma detection rate in trials enrolling predominantly women 
. Consistent with our findings of a trend toward increased risk in women after the reference date, a large population-based, cross-sectional study found rates of colorectal neoplasia in women to reach rates of those in men approximately 10 years later in life 
. A recent, large meta-analysis of 24 cohort studies, Luo et al. 
found significant heterogeneity by gender and noted a stronger association between DM and colon cancer among males (RR
1.47, 95% CI 1.15–1.86) than females (RR
1.08, 95% CI 1.00–1.17). Similarly, two meta-analyses that examined the association between BMI, which is strongly related to DM and colon cancer risk by gender, found a greater association in males than females 
. While it seems that higher quality evidence largely suggests that colon cancer risk is greater in men than in women, we suspect that lack of observation of gender effects in some meta-analyses and reports, despite a clear effect of DM, could be related to lack of examination of the temporal changes in risk we report here, in addition to other difficulties in accurately determining date of DM onset and, quality of the reported data (e.g. reliance on self-reports).
Gender differences in colon cancer risk suggest the potential for hormonal effects. Obesity is the most common co-morbidity of DM and is implicated in promotion of oncogenic processes 
. In the present study, diabetic subjects had a higher mean BMI at the reference date than those in the non-diabetic group. Obesity may differentially affect hormone levels in men and women, especially by reducing androgen levels in men. Obesity is a well-known risk factor for colorectal cancer 
, and lower androgen levels may also increase colorectal cancer risk in men 
. The increased colon cancer risk observed before DM onset in men, but not women, may be related to this physiological mechanism. Several studies also suggest that female sex hormones may be protective for colon cancer 
. Before menopause, hormonal cycling may delay the increase in risk for colon cancer noted in the present study among women with emergent DM. However, with advancing age, onset of menopause, and increased duration of DM, any advantages afforded by the female hormonal milieu may dissipate 
. While the increased colon cancer risk in men before DM onset may appear relatively modest, the societal and economic impact of these findings is amplified in the context of the pervasiveness of DM. An estimated 79 million people in the United States meet criteria for pre-diabetes, with over one million cases of DM diagnosed annually 
. The NNEH for colon cancer in diabetic men at time of DM onset is 263, suggesting that the pre-diabetic state is a risk factor for colon cancer on par with smoking for bladder cancer, where the NNEH is 727 
. Recognition of the increased risk for colon cancer in men before DM onset allows for potential intervention in the pre-diabetes state. Understanding the gender differences in colon cancer risk identifies the patients in which intervention during the pre-diabetes phase may have the greatest impact. Interventions such as weight control through diet and exercise may have a far reaching impact on the likelihood of colon cancer in pre-diabetic men.
The observational design of the present study results in the potential for certain types of bias. First, the percentage of diabetic subjects with 20 or more healthcare visits in the 2 years before the reference date was greater than that of non-diabetic subjects. Increased healthcare utilization by diabetic subjects raises the possibility of ascertainment bias. However, evidence indicates that there is no increased diligence in colon cancer screening in patients with emergent DM 
. Despite reports that diabetic individuals have higher rates of adenoma earlier in life, systematic early screening for diabetic patients is not currently recommended 
. Second, data were collected during routine clinical care and not in the context of a systematic research study with baseline patient information collected only at reference date. Thus, there is a possibility that patient covariates may have been impacted by outcome. This, however, would be expected to bias results towards the null rather than produce spurious associations. Third, we also note that cancer treatment and screening data were unavailable for the majority of patients. Fourth, we focused our analyses on colon cancer to avoid confounding as a result of the physiological differences in tumorigenesis in the colon and rectum, which may limit comparison of our findings to previous studies of colorectal cancer. Finally, the potential for immortal time bias needs to be acknowledged, as patients destined to develop DM could have developed rapidly progressing colon cancer and died before DM onset could be observed. Bias is introduced when such patients are misclassified into the “unexposed” group or are excluded from analyses. However, the impact of this sort of bias is likely to move the pre-diabetic effect observed toward null, and in such a case, men may be at even greater risk for colon cancer during the pre-diabetes phase than demonstrated here. On the other hand, this study also has several strengths. We capitalized on a unique institutional capacity for tracking individual patient data over time to accurately define DM onset and colon cancer risk using a complex algorithm and comprehensive administrative and clinical parameters, including laboratory measures. Use of clinical parameters is unique to the present study. Given the insidious onset of DM, our ability to track clinical DM diagnosis within the context of elements in the EMR and laboratory and administrative data was a major strength of the current study.
By accurately pinpointing date of clinical DM onset, we were able to assess the temporal relationship between DM and colon cancer risk and carefully analyze gender differences. We found that colon cancer risk is increased in diabetic men, but not women, before DM onset. Following DM onset, there was no association between DM and colon cancer risk in either gender. In pre-diabetic men, colon cancer risk increased over time, peaking near the time of DM onset, suggesting that the effects of the pre-diabetic state on colon cancer in men are cumulative. These results support the hyperinsulinemia hypothesis of carcinogenesis 
. It would be important to confirm these results in a well-conducted, prospective study, as the outcomes we report demonstrate an important temporal perspective regarding colon cancer risk and DM trajectory that has not been previously reported. If confirmed, the pre-diabetes phase may offer the greatest opportunity to implement an interventional or screening strategy to reduce risk of colon cancer in men.