| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2006. Published by Oxford University Press.
BRIEF COMMUNICATION |
Diabetes Mellitus and Risk of Colorectal Cancer in the Singapore Chinese Health Study
Affiliations of authors: Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore (AS, W-PK, H-PL); The Cancer Center, University of Minnesota, Minneapolis, MN (J-MY, MCY)
Correspondence to: Adeline Seow, MD, Department of Community, Occupational and Family Medicine, National University of Singapore, MD3, 16 Medical Dr., Singapore 117597, Singapore (e-mail: cofseowa{at}nus.edu.sg).
 |
ABSTRACT |
|---|
 TopNotes Abstract References |
|---|
The incidence of colorectal cancer is highest in populations that consume an energy-dense diet, have low intakes of vegetables and fruit, or lead a sedentary lifestyle. These factors may influence colorectal carcinogenesis via insulin pathways. We examined whether diabetes mellitus was associated with colorectal cancer in Singapore Chinese, whose body type and lifestyle profiles are distinct from those of Western populations. Between April 1993 and December 1998, 63 257 Singapore Chinese men and women aged 45 to 74 years were enrolled in a prospective study of diet and cancer. Each subject provided dietary, medical, and lifestyle information through an in-person interview. As of December 31, 2002, 636 incident colorectal cancer cases had been diagnosed. A history of physician-diagnosed diabetes was statistically significantly associated with colorectal cancer risk in both men (relative risk [RR] = 1.5, 95% confidence interval [CI] = 1.2 to 2.1) and women (RR = 1.4, 95% CI = 1.0 to 1.9). In stratified analyses, this association remained statistically significant among the subset of diabetics with high total calorie intake and low physical activity levels. Our results support the hypothesis that hyperinsulinemia may play a role in colorectal carcinogenesis, even in a relatively lean population.
There is convincing evidence across diverse populations that obesity and diets high in total energy, fat, protein or red meat, and carbohydrates elevate the risk of colorectal cancer (1–5). Conversely, higher intakes of fruit, vegetables, and an active lifestyle can reduce risk of this malignancy (1–8). Based on both observational and experimental study findings, a unifying hypothesis has been proposed in which insulin and insulin-like growth factors play a central role in colorectal carcinogenesis (9–14). Epidemiologic data suggest that a history of diabetes mellitus, and, in particular, type 2 diabetes (15), and impaired glucose tolerance are risk factors for colorectal cancer (16–22). Individuals with type 2 diabetes have peripheral resistance to insulin and develop hyperinsulinemia as a compensatory response (23,24), and this hyperinsulinemic state is believed to be the mechanism that underlies the association between diabetes and colorectal carcinogenesis (7,25–27).
Ethnic Chinese constitute more than three-quarters of Singapore's population and have experienced dramatic changes in lifestyle over the past few decades as a consequence of the country's rapid industrialization and rising affluence. Among these changes is a marked increase in total calorie and meat consumption (28) and a rise in obesity rates (29). The population-based estimate of the prevalence of diabetes mellitus among Singapore Chinese was 8.0% in 1998 (29), compared with global prevalence estimates of 6% in developed countries and 3.3% in developing countries (30). Between 1970 and 2000, age-standardized colon cancer incidence rates (per 100 000) increased from 11.6 to 26.6 in men and from 9.5 to 20.9 in women. Similar increases have been observed for rectal cancer in this population (31). We assessed whether a history of diabetes was associated with colorectal cancer in Singapore Chinese and investigated whether this association was modified by other factors possibly involved in the putative insulin–colorectal cancer pathway in a prospective study, the Singapore Chinese Health Study.
The Singapore Chinese Health Study is a population-based prospective cohort study of ethnic Chinese men and women, aged 45–74 years at baseline, who belong to either the Hokkien or the Cantonese dialect groups and live in government housing estates (which house 86% of all residents in Singapore) (32). A total of 63 257 individuals gave informed written consent and enrolled between April 1993 and December 1998. For the present analysis, we excluded 1937 individuals with a history of any invasive cancer (except nonmelanoma skin cancer) or in situ bladder cancer. The study was approved by the Institutional Review Boards of the University of Southern California and the National University of Singapore.
At recruitment, each participant completed an in-person interview using a structured questionnaire that requested information about demographic characteristics, height and weight, use of tobacco, usual physical activity, medical history, and family history of cancer. The questionnaire included a validated semiquantitative food frequency section listing 165 food items commonly consumed in the study population, from which we were able to derive average daily intake of calories and other nutrients using the Singapore Food Composition Database (32).
For each subject, person-years of follow-up were counted from the date of enrollment to the date of diagnosis of colorectal cancer, date of death, or December 31, 2002, whichever occurred first. We identified incident colorectal cancer cases through the Singapore Cancer Registry and deaths through the Singapore Registry of Births and Deaths. We used Cox proportional hazards modeling (33) to examine the association between diabetes mellitus and the risk of developing colorectal cancer. The proportionality assumption was tested using the method of Lin et al. (34) and found to be satisfied (P = .13). All models were adjusted for age at enrollment, year of enrollment, dialect group, and known risk factors for colorectal cancer (see footnote to Table 2). We also examined the association between diabetes and colorectal cancer in subjects stratified by sex, body mass index (BMI; <20 kg/m2, 20–23.9, 24–27.9, 
28), total calorie intake (below and above the median level of 1458.04 kcal/day), and vigorous work or strenuous physical activity (yes or no). Statistical analysis was conducted using SAS version 9.1 (SAS Institute Inc., Cary, NC) and Epilog for Windows version 1.0 (Epicenter Software, Pasadena, CA). All P values are two-sided.
|
Of the 61 320 cohort members who were free of cancer at baseline, 5469 (8.9%) reported a history of any physician-diagnosed diabetes mellitus. Diabetics and nondiabetics were similar in distribution by gender and familial history of colorectal cancer (Table 1). Compared with nondiabetics, diabetics were statistically significantly older and had slightly higher BMI levels, had less formal education, and engaged in less physical activity (Table 1). Diabetics also reported lower alcohol and total calorie consumption at baseline than nondiabetics (Table 1).
|
As of December 31, 2002 (mean follow-up time = 7.1 years), 636 subjects (284 women and 352 men) had developed colorectal cancer (391 colon and 245 rectal cancers), 97% of which were histopathologically confirmed. The mean age at diagnosis was 66.6 years, and the mean interval between entry into the study and cancer diagnosis was 4.4 years (range = <1 month to 9.5 years). The incidence rate of colorectal cancer was 208.9 per 100 000 person-years (90 cases) in diabetics and 140.2 per 100 000 person-years (546 cases) in nondiabetics, after adjustment for age and sex. Compared with control subjects, case patients were statistically significantly older, more likely to be male or to be smokers, had less formal education, and reported lower consumption of calories, less physical activity, and higher intake of alcohol at baseline (Table 1).
The risk of colorectal cancer after adjustment for age, sex, dialect group, and year of interview was 50% higher among diabetics than among nondiabetics (relative risk [RR] = 1.5, 95% confidence interval [CI] = 1.2 to 1.9). Further adjustment for level of education, BMI, cigarette smoking, alcohol consumption, physical activity, and familial history of colorectal cancer did not change the association (Table 2). The risk elevation was seen in both men (RR = 1.5, 95% CI = 1.2 to 2.1) and women (RR = 1.4, 95% CI = 1.0 to 1.9). The relative risk estimates were similar for both colon cancer (RR =1.5, 95% CI =1.1 to 2.0) and rectal cancer (RR =1.5, 95% CI = 1.0 to 2.1). To account for prevalent cases that may have been undetected at the time of recruitment, we repeated the analysis but restricted it to those diagnosed 2 or more years after entry into the cohort; this restriction did not materially affect the relative risk estimates (data not shown).
When cancer patients and control subjects were stratified by BMI (Table 2), diabetics had a 70% higher risk of developing colorectal cancer (P<.001) than nondiabetics among subjects with a BMI between 20 and 24 kg/m2. There was no trend suggesting increasing risk of colorectal cancer among diabetics in the higher BMI categories. A statistically significantly elevated relative risk of colorectal cancer among diabetics compared with nondiabetics was also observed among subjects with higher total caloric intake (RR =1.8, 95% CI = 1.3 to 2.4; Pinteraction = .10). When subjects were stratified by physical activity, an elevated risk of colorectal cancer among diabetics versus nondiabetics was observed only in those subjects with lower levels of physical activity (RR = 1.5, 95% CI = 1.2 to 1.9; Pinteraction = .16).
Our results are consistent with the growing body of epidemiologic evidence that links a history of diabetes mellitus (primarily type 2) with colorectal cancer risk (16). In two large U.S. prospective cohorts (17,18), investigators reported risk ratios of approximately 1.3 for colon cancer mortality among men and women with diabetes. In the Nurses' Health Study, a history of type 2 diabetes was associated with a statistically significant 43% increase in colorectal cancer risk (19). A statistically significant 60% elevation in colorectal cancer risk was associated with self-reported diabetes among Norwegian women but not men (20). In the EPIC-Norfolk study, diabetes was associated with a twofold increase in colorectal cancer risk in both males and females (21). More recently, Jee et al. (22) reported that mortality from colorectal cancer in a large Korean prospective cohort was increased by 30% among men with diabetes but was not elevated among women with diabetes and that risk of incident colorectal cancers was only slightly elevated among diabetics (RR = 1.11, 95% CI = 1.00 to 1.24 in men and RR = 1.17, 95% CI = 0.98 to 1.40 in women).
In stratified analyses we observed a statistically significant association between diabetes and colorectal cancer risk among individuals with higher calorie intake and lower levels of physical activity. This finding is consistent with higher levels of insulin resistance among these individuals (35–39), and this interaction requires further evaluation in other large studies. In addition, the association between diabetes and colorectal cancer risk was present even among individuals with BMI levels that are considerably lower than the average values in Western populations. In the Korean cohort (22), the association between fasting serum glucose and overall cancer mortality was consistent across BMI categories, and the association was most marked in those with BMI of 20–22.9 kg/m2. Both Asian populations (i.e., Koreans and Singapore Chinese) are generally lean, with the average BMI being about 23 kg/m2. By comparison, the average BMI in U.S. adults is 28 kg/m2 (40). Therefore, our data suggest that high BMI per se does not drive the diabetes–colorectal cancer association. It is conceivable that other aspects of adiposity that were not measured in this study, such as waist-to-hip ratio (a surrogate for visceral adipose tissue) are more important determinants of insulin resistance, as has been observed in other populations (41–43).
A limitation of this analysis is the use of self-report for physician-diagnosed diabetes. The proportion of cohort members who reported a history of diabetes (8.9%) is substantially lower than estimates of the prevalence in the general population (18.2% and 22.0% among male and female Singapore Chinese aged 50–59 years, respectively) based on an oral glucose tolerance test (29). However, this form of underreporting would attenuate a true association between diabetes and colorectal cancer. Also, the questionnaire was administered only once, at baseline, and any changes in physical activity or diet during follow-up were not captured. Detection bias is another concern, because it may be argued that diabetics would be under closer surveillance and more likely to have cancer detected than nondiabetics. However, the small size of Singapore and the even distribution of health care facilities that promote access by all segments of the population make this bias unlikely (44). In addition, all cases were ascertained through the population-based Cancer Registry, which maintains excellent coverage and has a "death certificate–only" rate of less than 1% (31).
In summary, we observed that diabetes mellitus was a risk factor for colorectal cancer in Singapore Chinese and that this association was statistically significant among those with high intake of total calories and lower levels of physical activity, both of which are independent predictors of high insulin levels. Our results provide support for an association between hyperinsulinemia and colorectal cancer, even in a relatively lean population.
|
NOTES |
|---|
|
TopNotesAbstractReferences |
|---|
Supported by grants R01 CA55069, R35 CA53890, R01 CA80205, and R01 CA98497 from the National Cancer Institute, Bethesda, MD.
We thank Ms. Low Siew Hong for supervising the field work of the Singapore Chinese Health Study and Ms. Kazuko Arakawa of the University of Southern California for the development and management of the cohort study database. We also thank the Singapore Cancer Registry for assistance with the identification of cancer outcomes.
|
REFERENCES |
|---|
|
TopNotesAbstractReferences |
|---|
(1) Potter JD. Nutrition and colorectal cancer. Cancer Causes Control 1996;7:127–46.[CrossRef][ISI][Medline]
(2) Giovannucci E. Modifiable risk factors for colon cancer. Gastroenterol Clin North Am 2002;31:925–43.[Medline]
(3) Satia-Abouta J, Galanko JA, Martin CF, Ammerman A, Sandler RS. Food groups and colon cancer risk in African-Americans and Caucasians. Int J Cancer 2004;109:728–36.[CrossRef][ISI][Medline]
(4) Lee HP, Gourley L, Duffy SW, Esteve J, Lee J, Day NE. Colorectal cancer and diet in an Asian population – a case-control study among Singapore Chinese. Int J Cancer 1989;43:1007–16.[ISI][Medline]
(5) Seow A, Quah SR, Nyam D, Straughan PT, Chua T, Aw TC. Food groups and the risk of colorectal carcinoma in an Asian population. Cancer 2002;95:2390–6.[CrossRef][ISI][Medline]
(6) International Agency for Research on Cancer. Weight control and physical activity. IARC Handbooks of Cancer Prevention, Vol 6. IARC Press, Lyon (France); 2002:85–94.
(7) Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004;4:579–91.[CrossRef][ISI][Medline]
(8) Colditz GA, Cannuscio CC, Frazier AL. Physical activity and reduced risk of colon cancer: implications for prevention. Cancer Causes Control 1997;8:649–67.[CrossRef][ISI][Medline]
(9) McKeown-Eyssen G. Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol Biomarkers Prev 1994;3:687–95.[Abstract]
(10) Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 2001;131 11 Suppl:3109S–20S.
(11) Giovannucci E. Nutrition, insulin, insulin-like growth factors and cancer. Horm Metab Res 2003;35:694–704.[CrossRef][ISI][Medline]
(12) Taha C, Klip A. The insulin signaling pathway. J Membr Biol 1999;169:1–12.[CrossRef][ISI][Medline]
(13) Pollak M. Insulin-like growth factor physiology and cancer risk. Eur J Cancer 2000;36:1224–8.[CrossRef][ISI][Medline]
(14) Komninou D, Ayonote A, Richie JP Jr, Rigas B. Insulin resistance and its contribution to colon carcinogenesis. Exp Biol Med (Maywood) 2003;228:396–405.
(15) American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2004;27:S5–10.
(16) Chang CK, Ulrich CM. Hyperinsulinaemia and hyperglycaemia: possible risk factors of colorectal cancer among diabetic patients. Diabetologia 2003;46:595–607.[ISI][Medline]
(17) Will JC, Galuska DA, Vinicor F, Calle EE. Colorectal cancer: another complication of diabetes mellitus? Am J Epidemiol 1998;147:816–25.
(18) Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol 2004;159:1160–7.
(19) Hu FB, Manson JE, Liu S, Hunter D, Colditz GA, Michels KB, et al. Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst 1999;91:542–7.
(20) Nilsen TL, Vatten LJ. Prospective study of colorectal cancer risk and physical activity, diabetes, blood glucose and BMI: exploring the hyperinsulinaemia hypothesis. Br J Cancer 2001;84:417–22.[CrossRef][ISI][Medline]
(21) Khaw KT, Wareham N, Bingham S, Lyben R, Welch A, Day N. Preliminary communication: glycated hemoglobin, diabetes, and incident colorectal cancer in men and women: a prospective analysis from the European Prospective Investigation into cancer—Norfolk study. Cancer Epidemiol Biomarkers Prev 2004;13:915–9.
(22) Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM. Fasting serum glucose level and cancer risk in Korean men and women. JAMA 2005;293:194–202.
(23) De Fronzo RA, Bonadonna RC, Ferrannini E. Pathogenesis of NIDDM. A balanced overview. Diabetes Care 1992;15:318–53.[Abstract]
(24) Le Roith D. Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities. Am J Med 2002;113:3S–11S.
(25) Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988;37:1595–607.[Abstract]
(26) Moller DE, Flier JS. Insulin resistance—mechanisms, syndromes, and implications. N Engl J Med 1991;325:938–48.[ISI][Medline]
(27) Bruce WR, Giacca A, Medline A. Possible mechanisms relating diet and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 2000;9:1271–79.
(28) Lee HP, Gourley L. Food availability in Singapore from 1961 to 1983: implications for health research. Food Nutr Bull 1987;8:50–4.
(29) Epidemiology and Disease Control Department, Ministry of Health, Singapore. National Health Survey 1998 (Report). Singapore (Singapore): Ministry of Health; 1999.
(30) King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025. Prevalence, numerical estimates and projections. Diabetes Care 1998;21:1414–31.[Abstract]
(31) Seow A, Koh WP, Chia KS, Shi LM, Lee HP, Shanmugaratnam R. Trends in cancer incidence in Singapore 1968–2002. Singapore Cancer Registry Report No. 6. Singapore (Singapore): Singapore Cancer Registry; 2004.
(32) Hankin JH, Stram DO, Arakawa K, Park S, Low SH, Lee HP, et al. Singapore Chinese Health Study: development, validation and calibration of the quantitative food frequency questionnaire. Nutr Cancer 2001;39:187–95.[CrossRef][ISI][Medline]
(33) Cox DR. Regression models and life tables. J R Stat Soc (B) 1972;34:187–202.
(34) Lin DY, Wei LJ. The robust inference for the proportional hazards model. J Am Stat Assoc 1989;84:1074–8.[CrossRef][ISI]
(35) Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988–1994. Arch Intern Med 2003;163:427–36.
(36) Marshall JA, Bessesen DH, Hamman RF. High saturated fat and low starch and fibre are associated with hyperinsulinaemia in a non-diabetic population: The San Luis Valley Diabetes Study. Diabetologia 1997;40:430–8.[CrossRef][ISI][Medline]
(37) Hu FB, van Dam RM, Liu S. Diet and risk of type II diabetes: the role of types of fat and carbohydrate. Diabetologia 2001;44:805–17.[CrossRef][ISI][Medline]
(38) Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415–28.[CrossRef][ISI][Medline]
(39) Carnethon MR, Loria CM, Hill JO, Sidney S, Savage PJ, Liu K. Risk factors for the metabolic syndrome. The Coronary Artery Risk Development in Young Adults (CARDIA) study, 1985–2001. Diabetes Care 2004;27:2707–15.
(40) Ogden CL, Fryar CD, Carroll MD, Flegal KM. Mean body weight, height, and body mass index, United States 1960–2002. Advance Data from Vital and Health Statistics 2004. Bethesda (MD): US Department of Health and Human Services; 2004:347.
(41) Schoen RE, Tangen CM, Kuller LH, Burke GL, Cushman M, Tracy RP, et al. Increased blood glucose and insulin, body size, and incident colorectal cancer. J Natl Cancer Inst 1999;91:1147–54.
(42) Takami R, Takami K, Takeda N, Nakashima K, Hayashi M, Akai A, et al. Body fatness and fat distribution as predictors of metabolic abnormalities and early carotid atherosclerosis. Diabetes Care 2001;24:1248–52.
(43) Snijder MB, Yudkin JS, Dekker JM, Heine RJ, Visser M, Jijpels G, et al. Trunk fat and leg fat have independent and opposite associations with fasting and postload glucose levels. Diabetes Care 2004;27:372–7.
(44) Lim MK. Shifting the burden of health care finance: a case study of public-private partnership in Singapore. Health Policy 2004;69:83–92.[CrossRef][ISI][Medline]
Manuscript received May 12, 2005; revised October 28, 2005; accepted November 21, 2005.
Correspondence about this Article
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2006 98: 1019.
This article has been cited by other articles:
|
|
 |
|
  X. Yang PhD, W. So MBChB, G. T.C. Ko MD, R. C.W. Ma MBChB, A. P.S. Kong MBChB, C.-C. Chow MBBS, P. C.Y. Tong PhD, and J. C.N. Chan MD Independent associations between low-density lipoprotein cholesterol and cancer among patients with type 2 diabetes mellitus Can. Med. Assoc. J., August 26, 2008; 179(5): 427 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H-L Wong, W-P Koh, N M Probst-Hensch, D Van den Berg, M C Yu, and S A Ingles Insulin-like growth factor-1 promoter polymorphisms and colorectal cancer: a functional genomics approach Gut, August 1, 2008; 57(8): 1090 - 1096. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Yang, W.-Y. So, R. C W Ma, G. T C Ko, A. P S Kong, Q. Wang, C. S Cockram, C.-C. Chow, J. C N Chan, and P. C Y Tong Predicting values of lipids and white blood cell count for all-site cancer in type 2 diabetes Endocr. Relat. Cancer, June 1, 2008; 15(2): 597 - 607. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-L. Sun, J.-M. Yuan, W. P. Koh, H.-P. Lee, and M. C. Yu Green tea and black tea consumption in relation to colorectal cancer risk: the Singapore Chinese Health Study Carcinogenesis, October 1, 2007; 28(10): 2143 - 2148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Giovannucci Metabolic syndrome, hyperinsulinemia, and colon cancer: a review Am. J. Clinical Nutrition, September 1, 2007; 86(3): 836S - 842S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kisfalvi, O. Rey, S. H. Young, J. Sinnett-Smith, and E. Rozengurt Insulin Potentiates Ca2+ Signaling and Phosphatidylinositol 4,5-Bisphosphate Hydrolysis Induced by Gq Protein-Coupled Receptor Agonists through an mTOR-Dependent Pathway Endocrinology, July 1, 2007; 148(7): 3246 - 3257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. L. Wong Re: Diabetes mellitus and risk of colorectal cancer in the Singapore Chinese Health Study. J Natl Cancer Inst, July 19, 2006; 98(14): 1019 - 1019. [Full Text] [PDF]
|
|
|
|
|
|
T. Pischon, P. H. Lahmann, H. Boeing, C. Friedenreich, T. Norat, A. Tjonneland, J. Halkjaer, K. Overvad, F. Clavel-Chapelon, M.-C. Boutron-Ruault, et al. Body Size and Risk of Colon and Rectal Cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst, July 5, 2006; 98(13): 920 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Irby, W. F. Anderson, D. E. Henson, and S. S. Devesa Emerging and widening colorectal carcinoma disparities between blacks and whites in the United States (1975-2002). Cancer Epidemiol. Biomarkers Prev., April 1, 2006; 15(4): 792 - 797. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||