Affiliations of authors: F. B. Hu, Department of Nutrition, Harvard School of Public Health, Boston, MA; J. E. Manson, Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory and Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston; S. Liu, Departments of Nutrition and Epidemiology, Harvard School of Public Health; D. Hunter, G. A. Colditz, K. B. Michels, Department of Epidemiology, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; F. E. Speizer, Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; E. Giovannucci, Department of Nutrition, Harvard School of Public Health, and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School.
Correspondence to: Frank B. Hu, M.D., Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115 (e-mail: frank.hu{at}channing.harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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Epidemiologic data on the association between diabetes and risk of colon cancer are sparse and inconclusive. When compared with the age-standardized cancer rates in the general populations, diabetics appear to have slightly elevated rates of colorectal cancer (3-5). However, these results are difficult to interpret because individuals in the cohorts may differ in many aspects (especially body mass index) from external comparison populations. A positive association between history of diabetes and colorectal cancer has been reported in several case-control studies (6-9), but not in all (10). Also, the positive association tended to be stronger for men than for women (6,7,10). However, the small number of colon cancer cases among diabetics (6-10), potential recall bias (6,7,10), lack of control for important confounders such as obesity and physical activity (7,10), and failure to consider the type or duration of diabetes (6,7,10) have hampered the interpretation of the findings. Recently, a prospective study (11) with 13 years of follow-up found a significant positive association between diabetes and incidence of colorectal cancer in men (relative risk [RR] = 1.30; 95% confidence interval [CI] = 1.03-1.65) and a weaker nonsignificant positive association in women (RR = 1.16; 95% CI = 0.87-1.53). However, diabetes was not associated with an increased risk of fatal colon cancer. This finding raises the question of detection or diagnostic bias because earlier and less aggressive cancers are typically more prone to heightened detection and surveillance that may occur among individuals with diabetes.
The present study, with 18 years of follow-up, examines the relationship of diabetes with the incidence of colorectal cancers among women enrolled in the Nurses' Health Study. We specifically examine this relationship by years since the diagnosis of diabetes because insulin levels may differ depending on earlier or later stage of type 2 diabetes.
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SUBJECTS AND METHODS |
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The Nurses' Health Study cohort was established in 1976 when 121 700 female registered nurses 30-55 years of age completed a mailed questionnaire on their medical histories and lifestyles. Every 2 years, follow-up questionnaires are sent to obtain updated information on risk factors and to identify newly diagnosed diseases. The validity of the biennial questionnaire on medical history and lifestyle factors has been described in detail previously (12). Beginning in 1980, validated food-frequency questionnaires have been used to assess dietary intakes at 2- to 4-year cycles (13). The participants in the present study included women who were free of diagnosed cancer at baseline in 1976 (n = 118 403). This study was approved by the Human Research Committee at the Brigham and Women's Hospital.
Assessment of Diabetes Mellitus
On the baseline and subsequent biennial questionnaires, we asked the participants if and when they had ever been diagnosed with diabetes (either insulin-dependent or non-insulin-dependent). At baseline, 2095 women reported a previous diagnosis of diabetes. During follow-up (1976-1992), an additional 5305 women reported a diagnosis. We excluded women who had diabetes before age 30 years because they were most likely to have type 1 diabetes (n = 331).
Self-reported diabetes was validated by a supplementary questionnaire regarding symptoms, diagnostic tests, and treatment of diabetes and confirmed by medical record review in a sample (14). We obtained medical records in a random sample of 84 participants who reported a diagnosis of diabetes. Of the 84 women, 71 provided permission for medical record review; medical records could be obtained for 62. An endocrinologist who was blinded to the information reported on the supplementary questionnaire reviewed the available records using the National Diabetes Data Group Criteria (15). The diagnosis of type 2 diabetes was confirmed by medical record review in 61 (98.4%) of the 62 women (14).
Identification of Cases of Colorectal Cancer
We identified cases of colorectal cancer through biennial questionnaires and medical record review (16). On each follow-up questionnaire, we asked whether cancer of the colon or rectum has been diagnosed during the previous 2 years. In addition to reports from next of kin, we also used the National Death Index and the U.S. Postal Service to identify fatalities; we estimate that more than 98% of deaths were ascertained (17). When a participant (or the next of kin for decedents) reported a diagnosis of cancer of the colon or rectum on our follow-up questionnaire, we asked her (or the next of kin) for permission to obtain hospital records and pathology reports pertaining to this diagnosis. A study physician blinded to the exposure information reviewed the medical records to extract information on the histologic type, the anatomic location, and the stage of the cancer. Proximal colon cancers were defined as those from the cecum to and including the splenic flexure, and distal colon cancers were defined as those in the descending and sigmoid colon. Advanced cancers were defined as those with evidence of metastasis (to regional lymph nodes or to distant organs) at diagnosis. Fatal cancers were defined as those diagnosed since 1976 but fatal by the end of the follow-up (June 1, 1994).
Statistical Analysis
Person-time for each participant was calculated from the date of return of the 1976
questionnaire to the date of colorectal cancer diagnosis, death from any cause, or June 1, 1994,
whichever came first. Diagnosis of diabetes was reported at baseline and updated every 2 years.
For incident diabetic cases (diabetes occurring during follow-up), diabetic person-years were
calculated from the diagnosis of the diabetes. For prevalent diabetic cases (diabetes at baseline),
diabetic person-years were calculated from the beginning of the study (1976). Women who
reported cancer on previous questionnaires were excluded from subsequent analyses. We
calculated incidence rates of colorectal cancer for women diagnosed with diabetes by dividing
the number of incident cases by the number of person-years of follow-up. The RR was computed
as the rate among women with diabetes divided by the rate among nondiabetics, with adjustment
for 5-year age categories. Years since diagnosis of diabetes was determined by questionnaire at
baseline and updated every 2 years. We classified years since diagnosis into four categories based
on the frequency distribution (no diabetes, 10 years, 11-15 years, and >15 years).
We used pooled logistic regression across the nine 2-year intervals (June 1976-June 1978 and
similar time periods in the following years: 1978-1980, 1980-1982, 1982-1984, 1984-1986,
1986-1988, 1988-1990, 1990-1992, and 1992-1994) (18), which is
asymptotically equivalent to time-varying Cox regression, to adjust simultaneously for potential
confounding variables, including age (age groups: <49, 50-54, 55-59, 60-64, 65 years
old); body mass index (10 categories); and menopausal status (premenopausal, postmenopausal
without hormone replacement, postmenopausal with past hormone replacement, and
postmenopausal with current hormone replacement). These variables were first assessed in 1976
and updated every 2 years. We also adjusted for multivitamin use (yes or no); alcohol
consumption (0, >0-4, 5-14, or
15 g/day); aspirin use (yes or no); and average hours per
week of moderate or vigorous activity (<1, 1-1.9, 2-3.9, 4-6.9, or
7). These variables
were first assessed in 1980 and updated every 2 to 4 years. We also adjusted for intake of red
meat (including beef as a main dish, beef in a sandwich or mixed dish, hamburger, hot dog,
processed meat, and bacon), which was assessed in 1980, 1984, 1986, and 1990. To best
represent long-term diet and reduce measurement error, we adjusted for cumulative averages of
red meat intake in the pooled logistic model (19). For example, 1980
meat intake was related to incident colorectal cancer from 1980 through 1984 and the average of
1980 and 1984 intakes was related to incident cases from 1984 through 1986. For variables that
were initially assessed in 1980, we replaced missing values in 1976 with the values from 1980. In
addition, we controlled for pack-years of smoking before age 30 because it was more predictive
of colon cancer than was current or lifetime smoking (20). We also
controlled for parental history of colorectal cancer. All reported P values were derived
from the two-sided Wald test.
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RESULTS |
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Table 1 shows baseline characteristics for all self-reported diabetics
(n = 7069) and nondiabetics (n = 111,003) up to 1992. Smoking rate, parental
history of colorectal cancer, aspirin use, multivitamin supplement use, and intakes of red meat,
dietary fats, and folate were similar between diabetics and nondiabetics. Diabetic women were
slightly less active and substantially heavier. Utilization of colonoscopy or sigmoidoscopy by
1992 was comparable among diabetic and nondiabetic women.
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The positive associations were strongest among women whose diabetes had been diagnosed
for 11-15 years (Table 3). Compared with nondiabetics, the multivariate
RRs for this group were 2.30 (95% CI = 1.43-3.71; P = .0006) for
colorectal cancer, 2.83 (95% CI = 1.67-4.78; P = .0001) for colon
cancer, 2.25 (95% CI = 1.11-4.58; P = .02) for advanced
colorectal cancer, and 3.96 (95% CI = 1.72-9.12; P = .001) for
fatal colorectal cancer. (We did not analyze rectal cancer because of the small number of cases.)
These RRs diminished among women whose diabetes had been diagnosed for more than 15
years, although positive associations remained.
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DISCUSSION |
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Physician-diagnosed diabetes was reported by the participants, but with high accuracy according to additional information obtained from supplemental questionnaires asking about symptoms and treatment and a validation study using medical record review (14). Some diabetics may have been undiagnosed, but this percentage would be relatively small compared with that in the general population because of the nurses' relative greater access to medical care. Moreover, misclassification in the diagnosis of diabetes would tend to attenuate any true association between diabetes and colon cancer. In additional analyses, we found a similar positive association when confirmed diabetes (based on women who returned the supplementary questionnaires) was used as an exposure variable.
Detection bias is the most plausible alternative explanation for the observed positive association because, among diabetics, early colorectal cancer may be more likely to be diagnosed as a result of a heightened screening and detection. Several lines of evidence, however, argue against this explanation. First, we found that the positive association was stronger for advanced and fatal colorectal cancers, which would be less prone to detection and diagnostic biases. Second, the increased risk was stronger among women who had diabetes for a considerable amount of time (i.e., 11-15 years). Enhanced surveillance and detection are probably more likely to occur in the first several years following diagnosis. Finally, utilization of colonoscopy or sigmiodoscopy was comparable among diabetic and nondiabetic women (28% and 26%, respectively, by 1992).
Confounding is another concern but was unlikely to explain our findings. As shown in Table
1, colon cancer risk profiles were generally similar between diabetics and
nondiabetics. Body mass index and lack of physical activity are potentially the most important
known confounders for the positive association between diabetes and colon cancer. However, a
statistically significant association persists even after adjustment for these variables, both of
which were assessed multiple times during follow-up and the repeated assessments were used in
the analyses. Some of the covariates, such as alcohol consumption, red meat intake, and
multivitamin use, were first measured in 1980 rather than in 1976. However, when we controlled
for these variables, the multivariate RRs were similar to the age-adjusted ones; thus, any
uncontrolled confounding due to incomplete data for these variables was unlikely to account for
the observed association between diabetes and colorectal cancer. Also, analyses using 1980 as
baseline yielded similar results.
Previous epidemiologic studies of diabetes and colorectal cancer have suggested a positive association, but the data are not entirely consistent. Two studies of diabetic patients using external population comparisons (3,5) have found a small and nonsignificant excess in rate of colorectal cancer in men but not in women. In a case-control study conducted in Italy, history of diabetes was significantly associated with risk of both colon cancer (odds ratio [OR] = 1.7) and rectal cancer (OR = 1.5) (8). In a subsequent larger case-control study conducted by the same group (9), the OR was 1.2 for colon cancer and 1.5 for rectal cancer. The former study found the strongest association among subjects whose diabetes had been diagnosed for 5-9 years, and the latter found a stronger association among subjects who had diabetes for 10 years or more. Neither study examined the association among women who had diabetes for a longer duration. In our study, we observed a weaker positive association for rectal cancer, but the number of rectal cancer cases among diabetics was small (nine cases). In parallel, associations between obesity and a sedentary lifestyle have usually been observed with colon cancer but not with rectal cancer (1). In addition, we found that the positive association for colorectal cancer was greatest within 11-15 years after diagnosis of diabetes and diminished after 15 years of diagnosis (see the explanations below). In the only previous prospective cohort study (11), the RRs of colorectal cancer were 1.30 for men and 1.16 for women. However, in this study, status of diabetes was not updated during follow-up. The observed weaker associations were probably a result of prolonged follow-up.
Hyperinsulinemia has been proposed to be the underlying link between diabetes and colon cancer (1). This insulin-colon cancer hypothesis is based on strong epidemiologic evidence that major environmental risk factors for type 2 diabetes (such as high body mass index, increased central obesity, sedentary lifestyle, and possibly higher intake of refined carbohydrates) are remarkably similar to those for colon cancer. There is strong evidence that these factors are important determinants of insulin resistance and hyperinsulinemia (21,22). Since insulin is an important growth factor for colonic mucosal cells and colonic cancer cells and a mitogen of tumor cell growth in vitro (23,24) and a colon tumor promoter in vivo (25), high plasma insulin levels may mediate the effect of these factors on the risk of colon cancer. Based on the insulin hypothesis, the expected relationship between type 2 diabetes and colon cancer is complex because, at the early stage of type 2 diabetes, hyperinsulinemia exists but, in later stages, pancreatic beta cell malfunction leads to a hypoinsulinemic response. As expected a priori, we found that the increased risk of colorectal cancer diminished among women who had had diabetes for a long duration (i.e., after 15 years from diagnosis). However, the insulin hypothesis cannot be directly confirmed by these data because we did not measure plasma insulin levels and, also, the induction period for an effect of insulin on colon cancer risk is unknown.
Another line of evidence for the proposed insulin-colon cancer relationship is the observation that a high glycemic index diet, which has been associated with risk of type 2 diabetes (26,27) and coronary heart disease (28), is also associated with risk of colon cancer (29). A dietary glycemic index is used to quantify the response of blood glucose and insulin to a diet (30,31). The higher the glycemic index, the greater the glycemic and insulinemic responses. In a case-control study, Slattery et al. (29) found a positive association between dietary glycemic index and colon cancer. Higher intake of refined sugars, which produces a sharp glycemic response due to readily absorbable glucose, has been associated with increased risk of colon cancer in one prospective cohort study (32) and a number of case-control studies (33-37). In addition, higher intake of rapidly digestible starches, such as breads, potatoes, cakes, and dessert, may also increase risk of colon cancer (38). These findings suggest that glycemic and insulinemic responses may contribute to the effect of diet on the risk of colon cancer.
Besides insulin, several other mechanisms for the positive association have been proposed, including elevated levels of fecal bile acid associated with increased blood glucose and triglyceride levels (2) and slower bowel transit (11), which contributes to increased exposure to toxic substances and increased production of carcinogenic bile acids among diabetics.
In conclusion, our data provide support for the hypothesis that type 2 diabetes is associated with increased risk of colon cancer in women. These findings provide further epidemiologic evidence for the hypothesis that hyperinsulinemia, a compensatory response to insulin resistance, may be an underlying pathway for the development of colon cancer.
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NOTES |
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We are indebted to the participants in the Nurses' Health Study for their continuing outstanding level of cooperation; to Karen Corsano, Gary Chase, and Barbara Egan for their unfailing help; and to Drs. Walter Willett and Meir Stampfer for helpful comments.
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Manuscript received September 17, 1998; revised December 21, 1998; accepted December 31, 1998.
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