Previous studies have shown a positive association between type 2 diabetes (T2D) and colorectal cancer (CRC) risk. However, it is uncertain whether this association differs by duration of T2D or sex. We thus investigated the associations of T2D and its duration with the risk of incident CRC.
We followed 87,523 women from the Nurses’ Health Study (1980–2012) and 47,240 men from the Health Professionals Follow-up Study (1986–2012). Data on physician-diagnosed T2D was collected at baseline with a questionnaire and updated biennially. Cox regression models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
We documented 3000 CRC cases during up to 32 years of follow-up. Among men, T2D was associated with increased risk of CRC compared to those without T2D (HR: 1.42; 95% CI: 1.12–1.81). This positive association persisted in sensitivity analyses by excluding CRC identified within 1 year of diabetes diagnosis and patients with T2D who used hypoglycaemic medications. Among women, T2D was positively, but not statistically significantly, associated with CRC risk (HR: 1.17; 95% CI: 0.98–1.39).
Our findings support that T2D was associated with a moderately higher risk of developing CRC in men; a weaker, nonsignificant positive association was observed in women.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $32.88 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 62, 10–29 (2012).
Torre, L. A. et al. Global cancer statistics, 2012. CA Cancer J. Clin. 65, 87–108 (2015).
Campbell, P. T. et al. Prospective study reveals associations between colorectal cancer and type 2 diabetes mellitus or insulin use in men. Gastroenterology 139, 1138–1146 (2010).
Cavicchia, P. P. et al. Racial disparities in colorectal cancer incidence by type 2 diabetes mellitus status. Cancer Causes Control 24, 277–285 (2013).
Flood, A., Strayer, L., Schairer, C. & Schatzkin, A. Diabetes and risk of incident colorectal cancer in a prospective cohort of women. Cancer Causes Control 21, 1277–1284 (2010).
He, J. et al. The association of diabetes with colorectal cancer risk: the multiethnic cohort. Br. J. Cancer 103, 120–126 (2010).
Hu, F. B. et al. Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J. Natl. Cancer Inst. 91, 542–547 (1999).
Larsson, S. C., Giovannucci, E. & Wolk, A. Diabetes and colorectal cancer incidence in the cohort of Swedish men. Diabetes Care 28, 1805–1807 (2005).
Larsson, S. C., Orsini, N. & Wolk, A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J. Natl. Cancer Inst. 97, 1679–1687 (2005).
Nilsen, T. I. & Vatten, L. J. Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis. Br. J. Cancer 84, 417–422 (2001).
Peeters, P. J., Bazelier, M. T., Leufkens, H. G., de Vries, F. & De Bruin, M. L. The risk of colorectal cancer in patients with type 2 diabetes: associations with treatment stage and obesity. Diabetes Care 38, 495–502 (2015).
Sun, L. & Yu, S. Diabetes mellitus is an independent risk factor for colorectal cancer. Dig. Dis. Sci. 57, 1586–1597 (2012).
Yang, Y. X., Hennessy, S. & Lewis, J. D. Type 2 diabetes mellitus and the risk of colorectal cancer. Clin. Gastroenterol. Hepatol. 3, 587–594 (2005).
Seow, A., Yuan, J. M., Koh, W. P., Lee, H. P. & Yu, M. C. Diabetes mellitus and risk of colorectal cancer in the Singapore Chinese Health Study. J. Natl. Cancer Inst. 98, 135–138 (2006).
Lee, M. S. et al. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer 11, 20 (2011).
Limburg, P. J. et al. Diabetes mellitus and subsite-specific colorectal cancer risks in the Iowa Women’s Health Study. Cancer Epidemiol. Biomark. Prev. 14, 133–137 (2005).
Coughlin, S. S., Calle, E. E., Teras, L. R., Petrelli, J. & Thun, M. J. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am. J. Epidemiol. 159, 1160–1167 (2004).
Inoue, M. et al. Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch. Intern. Med. 166, 1871–1877 (2006).
de Kort, S. et al. Diabetes mellitus type 2 and subsite-specific colorectal cancer risk in men and women: results from the Netherlands Cohort Study on diet and cancer. Eur. J. Gastroenterol. Hepatol. 28, 896–903 (2016).
Limburg, P. J. et al. Clinically confirmed type 2 diabetes mellitus and colorectal cancer risk: a population-based, retrospective cohort study. Am. J. Gastroenterol. 101, 1872–1879 (2006).
Kuriki, K., Hirose, K. & Tajima, K. Diabetes and cancer risk for all and specific sites among Japanese men and women. Eur. J. Cancer Prev. 16, 83–89 (2007).
Ren, X. et al. Type 2 diabetes mellitus associated with increased risk for colorectal cancer: evidence from an international ecological study and population-based risk analysis in China. Public Health 123, 540–544 (2009).
Tabak, A. G. et al. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet 373, 2215–2221 (2009).
Giovannucci, E. Insulin and colon cancer. Cancer Causes Control 6, 164–179 (1995).
Vigneri, P., Frasca, F., Sciacca, L., Pandini, G. & Vigneri, R. Diabetes and cancer. Endocr. Relat. Cancer 16, 1103–1123 (2009).
Luo, W., Cao, Y., Liao, C. & Gao, F. Diabetes mellitus and the incidence and mortality of colorectal cancer: a meta-analysis of 24 cohort studies. Colorectal Dis. 14, 1307–1312 (2012).
Guraya, S. Y. Association of type 2 diabetes mellitus and the risk of colorectal cancer: a meta-analysis and systematic review. World J. Gastroenterol. 21, 6026–6031 (2015).
Guraya, S. Y. & Eltinay, O. E. Higher prevalence in young population and rightward shift of colorectal carcinoma. Saudi. Med. J. 27, 1391–1393 (2006).
Tsilidis, K. K., Kasimis, J. C., Lopez, D. S., Ntzani, E. E. & Ioannidis, J. P. Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 350, g7607 (2015).
Clendenen, T. V. et al. Postmenopausal levels of endogenous sex hormones and risk of colorectal cancer. Cancer Epidemiol. Biomark. Prev. 18, 275–281 (2009).
Falk, R. T. et al. Estrogen metabolites are not associated with colorectal cancer risk in postmenopausal women. Cancer Epidemiol. Biomark. Prev. 24, 1419–1422 (2015).
Gunter, M. J. et al. Insulin, insulin-like growth factor-I, endogenous estradiol, and risk of colorectal cancer in postmenopausal women. Cancer Res. 68, 329–337 (2008).
Lin, J. H. et al. Association between sex hormones and colorectal cancer risk in men and women. Clin. Gastroenterol. Hepatol. 11, 419–424 e411 (2013).
Murphy, N. et al. A prospective evaluation of endogenous sex hormone levels and colorectal cancer risk in postmenopausal women. J. Natl. Cancer. Inst. 107; https://doi.org/10.1093/jnci/djv210 (2015).
Shin, C. M. et al. Association among obesity, metabolic health, and the risk for colorectal cancer in the general population in Korea using the National Health Insurance Service-National Sample Cohort. Dis. Colon Rectum 60, 1192–1200 (2017).
Colditz, G. A. et al. Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am. J. Epidemiol. 123, 894–900 (1986).
Simon, T. G. et al. Diabetes, metabolic comorbidities, and risk of hepatocellular carcinoma: results from two prospective cohort studies. Hepatology 67, 1797–1806 (2018).
Cornelis, M. C. et al. Joint effects of common genetic variants on the risk for type 2 diabetes in U.S. men and women of European ancestry. Ann. Intern. Med. 150, 541–550 (2009).
Manson, J. E. et al. Physical activity and incidence of non-insulin-dependent diabetes mellitus in women. Lancet 338, 774–778 (1991).
Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes 28, 1039–1057 (1979).
Hu, F. B. et al. Physical activity and television watching in relation to risk for type 2 diabetes mellitus in men. Arch. Intern. Med. 161, 1542–1548 (2001).
Willett, W. C. et al. Reproducibility and validity of a semiquantitative food frequency questionnaire. Am. J. Epidemiol. 122, 51–65 (1985).
Wu, K., Willett, W. C., Fuchs, C. S., Colditz, G. A. & Giovannucci, E. L. Calcium intake and risk of colon cancer in women and men. J. Natl. Cancer Inst. 94, 437–446 (2002).
Rimm, E. B. et al. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am. J. Epidemiol. 135, 1114–1126 (1992). discussion 1127–1136.
Salvini, S. et al. Food-based validation of a dietary questionnaire: the effects of week-to-week variation in food consumption. Int. J. Epidemiol. 18, 858–867 (1989).
Feskanich, D. et al. Reproducibility and validity of food intake measurements from a semiquantitative food frequency questionnaire. J. Am. Diet. Assoc. 93, 790–796 (1993).
Willett, W. C. et al. Dietary fat and fiber in relation to risk of breast cancer. An 8-year follow-up. JAMA 268, 2037–2044 (1992).
Cochran, W. G. The combination of estimates from different experiments. Biometrics 10, 101–129 (1954).
Facchini, F., Chen, Y. D. & Reaven, G. M. Light-to-moderate alcohol intake is associated with enhanced insulin sensitivity. Diabetes Care 17, 115–119 (1994).
Kiechl, S. et al. Insulin sensitivity and regular alcohol consumption: large, prospective, cross sectional population study (Bruneck study). BMJ 313, 1040–1044 (1996).
Hamasaki, H. et al. Daily physical activity assessed by a triaxial accelerometer is beneficially associated with waist circumference, serum triglycerides, and insulin resistance in Japanese patients with prediabetes or untreated early type 2 diabetes. J Diabetes Res. 2015, 526201 (2015).
Cohen, F. J., Neslusan, C. A., Conklin, J. E. & Song, X. Recent antihyperglycemic prescribing trends for US privately insured patients with type 2 diabetes. Diabetes Care 26, 1847–1851 (2003).
Hoerger, T. J., Segel, J. E., Gregg, E. W. & Saaddine, J. B. Is glycemic control improving in U.S. adults? Diabetes Care 31, 81–86 (2008).
Rondini, E. A., Harvey, A. E., Steibel, J. P., Hursting, S. D. & Fenton, J. I. Energy balance modulates colon tumor growth: interactive roles of insulin and estrogen. Mol. Carcinog. 50, 370–382 (2011).
Geer, E. B. & Shen, W. Gender differences in insulin resistance, body composition, and energy balance. Gend. Med. 6(Suppl 1), 60–75 (2009).
Chlebowski, R. T. et al. Estrogen plus progestin and colorectal cancer in postmenopausal women. N. Engl. J. Med. 350, 991–1004 (2004).
Sainz, J. et al. Effect of type 2 diabetes predisposing genetic variants on colorectal cancer risk. J. Clin. Endocrinol. Metab. 97, E845–E851 (2012).
Kramer, H. U., Schottker, B., Raum, E. & Brenner, H. Type 2 diabetes mellitus and colorectal cancer: meta-analysis on sex-specific differences. Eur. J. Cancer 48, 1269–1282 (2012).
Bell, R. A. et al. Associations between alcohol consumption and insulin sensitivity and cardiovascular disease risk factors: the Insulin Resistance and Atherosclerosis Study. Diabetes Care 23, 1630–1636 (2000).
Klarich, D. S., Brasser, S. M. & Hong, M. Y. Moderate alcohol consumption and colorectal cancer risk. Alcohol. Clin. Exp. Res. 39, 1280–1291 (2015).
Kontou, N. et al. Alcohol consumption and colorectal cancer in a Mediterranean population: a case-control study. Dis. Colon Rectum 55, 703–710 (2012).
Park, J. Y. et al. Baseline alcohol consumption, type of alcoholic beverage and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition-Norfolk study. Cancer Epidemiol. 33, 347–354 (2009).
Ma, J. et al. A prospective study of plasma C-peptide and colorectal cancer risk in men. J. Natl. Cancer Inst. 96, 546–553 (2004).
Yin, S., Bai, H. & Jing, D. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients: a systemic review and meta-analysis. Diagn. Pathol. 9, 91 (2014).
Liu, F. et al. Metformin therapy and risk of colorectal adenomas and colorectal cancer in type 2 diabetes mellitus patients: a systematic review and meta-analysis. Oncotarget 8, 16017–16026 (2017).
Johnson, J. A., Bowker, S. L., Richardson, K. & Marra, C. A. Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias. Diabetologia 54, 2263–2271 (2011).
We would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: A.L., A.Z., A.R., C.A., C.O., C.T., D.E., F.L., G.A., I.D., I.L., I.N., I.A., K.Y., L.A., M.E., M.D., M.A., M.I., N.E., N.H., N.J., N.Y., N.C., N.D., O.H., O.K., O.R., P.A., R.I., S.C., T.N., T.X., V.A., W.A., W.Y.