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Diabetes Care 28:1805-1807, 2005
© 2005 by the American Diabetes Association, Inc.

Pathophysiology/Complications
Brief Report

Diabetes and Colorectal Cancer Incidence in the Cohort of Swedish Men

Susanna C. Larsson, MSC1, Edward Giovannucci, MD2,3 and Alicja Wolk, DMSC1

1 Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
2 Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts
3 Department of Medicine, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Susanna C. Larsson, Division of Nutritional Epidemiology, The National Institute of Environmental Medicine, Karolinska Institutet, P.O. Box 210, SE-171 77 Stockholm, Sweden. E-mail: susanna.larsson{at}imm.ki.se

Abbreviations: COSM, Cohort of Swedish Men • RR, rate ratio


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 
Dietary and lifestyle factors related to insulin resistance and hyperinsulinemia, including a westernized diet, physical inactivity, and obesity, have been linked to increased colorectal cancer risk (1,2). These observations support the hypothesis that hyperinsulinemia (3) or factors associated with insulin resistance, such as hyperglycemia or hypertriglyceridemia (4), may play a role in colorectal carcinogenesis. Epidemiologic studies have observed an elevated risk of colorectal cancer associated with high circulating insulin and C-peptide (a marker of insulin secretion) concentrations (5–7). Also, a recent study (8) reported that chronic insulin therapy was related to a significant increased risk of colorectal cancer among patients with type 2 diabetes.

Some, but not all, epidemiologic studies have observed an increased risk of colorectal cancer among people with diabetes (9). However, several previous investigations were limited by small sample size and an inability to account for important covariates (9). In addition, few studies have reported on diabetes in relation to subsites in the colon, and the findings have been conflicting (10–13). We therefore examined the relationship between self-reported diabetes and risk of colorectal cancer overall and by subsite in the COSM (Cohort of Swedish Men).


   RESEARCH DESIGN AND METHODS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
RESULTS
 CONCLUSIONS
 References
 
The COSM was initiated in the autumn of 1997 when all men aged 45–79 years residing in Västmanland and Örebro counties in central Sweden received an invitation to participate in the study along with a questionnaire. Among 100,303 eligible men, 48,850 responded to the questionnaire. Information on demographic and lifestyle factors, diet, and medical history (including diabetes) was obtained from the mailed questionnaire.

For this analysis, we excluded men with missing or erroneous National Registration Numbers (n = 260), men who returned an incomplete questionnaire (n = 92), and men with a previously diagnosed cancer at baseline (n = 2,592). Men who reported onset of diabetes before age 30 years were also excluded (n = 356) because they were more likely to have type 1 diabetes. Thus, 45,550 men were followed up until a diagnosis of colorectal cancer or death, or until 30 June 2004.

Cox proportional hazards models (14) stratified by age in months were used to estimate the rate ratios (RRs). In stratified analyses, we evaluated whether the association between diabetes and colorectal cancer was modified by physical activity (<1, 1–3, and ≥4 h/week), BMI (<25 and ≥25 kg/m2), and waist circumference (<95 and ≥95 cm). The likelihood ratio test was used to assess the significance of interactions. Statistical analysis was conducted using SAS software (SAS Institute, Cary, NC).


   RESULTS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
CONCLUSIONS
 References
 
On average, men with reported diabetes were older, had a lower educational attainment, had a higher BMI, and were more likely to smoke and use aspirin compared with nondiabetic men. Also, men with diabetes were less likely to exercise and to use multivitamins. Consumption of fruits, vegetables, dairy foods, and red meat was similar among diabetic and nondiabetic men.

During a mean follow-up of 6.2 years, 411 incident colorectal cancer cases occurred. Of these cancers, 98 were located in the proximal colon, 92 in the distal colon, and 156 in the rectum (subsite information was unavailable for 65 cancers). In both age-adjusted and multivariate analyses, reported diabetes was associated with a significant increased risk of colorectal cancer (Table 1). After controlling for potential confounders, the RR was 1.49 (95% CI 1.14–1.96). Further adjustment for waist circumference did not alter the findings materially (RR 1.48 [1.13–1.94]). Diabetes was related to statistically significant increased risk of both colon and rectal cancer (Table 1). Risk was elevated for proximal colon and distal colon cancer, although the results were not significant.


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  		Table 1— Diabetes and RRs of incident colorectal cancer overall and by cancer subsite in the COSM

 
We conducted multivariate analyses within strata of physical activity, BMI, and waist circumference. We observed that the positive association between diabetes and colorectal cancer risk persisted in all subgroups (data not shown), and there was no apparent modification of the relationship by these factors (P > 0.25 for all interaction tests).


   CONCLUSIONS
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
References
 
In this large population-based cohort, we found that men with diabetes had a statistically significant 49% increased risk of colorectal cancer after taking into account a large number of potential confounders. The excess cancer risk among diabetic men was observed for all subsites in the colorectum.

Our findings are consistent with most previous studies, showing an ~20–60% increase in colorectal cancer risk in subjects with diabetes (9,13). To our knowledge, only four studies have investigated whether the association with diabetes varies according to subsite in the colon (10,11,12,13). In a case-control study conducted in Hawaii (11), history of diabetes was associated with a significant increased risk of distal colon cancer but not of proximal colon or rectal cancer in both men and women. In contrast, the Nurses’ Health Study (12) and the Iowa Women’s Health Study (13) found history of diabetes to be more strongly associated with proximal colon cancer, although the Nurses’ Health Study (12) showed a nonsignificant positive association also with distal colon can-cer. Neither of those two cohorts observed an association with rectal cancer, but the number of rectal cancer cases was limited (nine cases in each cohort). A study of diabetic patients using external population comparisons (10) reported significant excess risk throughout the colorectum.

The strengths of our study include a population-based and prospective design, large size, and detailed information on potential risk factors for colorectal cancer. Because of the relatively large number of colorectal cancer cases, we were able to examine the association with diabetes by subsite. Our study is limited by the reliance on self-reported information on diabetes. We were unable to distinguish between type 1 and type 2 diabetes, even though we excluded men with probable type 1 diabetes. The possibility of uncontrolled or residual confounding cannot be entirely eliminated. However, we were able to adjust for multiple potential confounders, and we observed little difference between the age-adjusted and multivariate models.

In conclusion, our findings based on a large population-based cohort of men provide evidence that diabetes may increase the risk of colorectal cancer. These results support the hypothesis that hyperinsulinemia or factors related to insulin resistance may play a role in colorectal cancer etiology.


   Acknowledgments
 
Grant support for this study was provided by the Swedish Research Council/Longitudinal Studies, the Swedish Cancer Foundation, and the Swedish Foundation for International Cooperation in Research and Higher Education (STINT).


   Footnotes
 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Received for publication February 17, 2005. Accepted for publication March 30, 2005.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS
 RESULTS
 CONCLUSIONS
 References
 

  1. World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR): Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, DC, WCRF/AICR, 1997
  2. Giovannucci E: Modifiable risk factors for colon cancer. Gastroenterol Clin North Am 31:925–943, 2002[Medline]
  3. Giovannucci E: Insulin and colon cancer. Cancer Causes Control 6:164–179, 1995[Medline]
  4. McKeown-Eyssen G: Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol Biomarkers Prev 3:687–695, 1994[Abstract]
  5. Kaaks R, Toniolo P, Akhmedkhanov A, Lukanova A, Biessy C, Dechaud H, Rinaldi S, Zeleniuch-Jacquotte A, Shore RE, Riboli E: Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 92:1592–1600, 2000[Abstract/Free Full Text]
  6. Schoen RE, Tangen CM, Kuller LH, Burke GL, Cushman M, Tracy RP, Dobs A, Savage PJ: Increased blood glucose and insulin, body size, and incident colorectal cancer. J Natl Cancer Inst 91:1147–1154, 1999[Abstract/Free Full Text]
  7. Ma J, Giovannucci E, Pollak M, Leavitt A, Tao Y, Gaziano JM, Stampfer MJ: A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst 96:546–553, 2004[Abstract/Free Full Text]
  8. Yang YX, Hennessy S, Lewis JD: Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 127:1044–1050, 2004[Medline]
  9. Chang CK, Ulrich CM: Hyperinsulinaemia and hyperglycaemia: possible risk factors of colorectal cancer among diabetic patients. Diabetologia 46:595–607, 2003[Medline]
  10. Weiderpass E, Gridley G, Nyren O, Ekbom A, Persson I, Adami HO: Diabetes mellitus and risk of large bowel cancer (Letter). J Natl Cancer Inst 89:660–661, 1997[Free Full Text]
  11. Le Marchand L, Wilkens LR, Kolonel LN, Hankin JH, Lyu LC: Associations of sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with the risk of colorectal cancer. Cancer Res 57:4787–4794, 1997[Abstract/Free Full Text]
  12. Hu FB, Manson JE, Liu S, Hunter D, Colditz GA, Michels KB, Speizer FE, Giovannucci E: Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst 91:542–547, 1999[Abstract/Free Full Text]
  13. Limburg PJ, Anderson KE, Johnson TW, Jacobs DR Jr, Lazovich D, Hong CP, Nicodemus KK, Folsom AR: Diabetes mellitus and subsite-specific colorectal cancer risks in the Iowa Women’s Health Study. Cancer Epidemiol Biomarkers Prev 14:133–137, 2005[Abstract/Free Full Text]
  14. Cox DR, Oakes D: Analysis of Survival Data. London, Chapman and Hall, 1984

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