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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Obesity and insulin resistance are associated with the risk of colon cancer. Adenomatous colonic polyps are precancerous lesions of colon cancer. We investigated whether BMI and the metabolic syndrome are associated with the presence of adenomatous colonic polyps in Korean men. Anthropometric measurements, metabolic risk factors, and colonoscopic pathologic findings were assessed in 1,898 men who underwent routine colonoscopy at the Health Promotion Center of Asan Medical Center in 2005. The modified National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) and International Diabetes Federation (IDF) criteria were used for the definition of the metabolic syndrome. Multiple logistic regression analysis was used to evaluate the association between BMI and the metabolic syndrome and adenomatous polyps. Compared with men in the 1st quintile of the BMI, the adjusted odds ratio (OR) and 95% confidence interval (CI) for adenomatous polyps in men in the 2nd, 3rd, 4th, and 5th quintiles of the BMI were 1.55 (1.10–2.19), 1.57 (1.10–2.24), 1.94 (1.34–2.81), and 1.99 (1.31–3.01), respectively (P for trend <0.0001). Men with triglycerides (TGs) ≥150 mg/dl were significantly more likely to have adenomatous polyps than were men with TG <150 mg/dl (OR 1.29; 95% CI 1.03–1.62). As a function of the number of metabolic risk factors, the ORs for adenomatous polyps were 1.41 (1.03–1.93), 1.52 (1.08–2.12), 1.46 (1.01–2.12), and 1.77 (1.08–2.90) for 1, 2, 3, and ≥4 risk factors, respectively (P for trend <0.05). Adenomatous colonic polyps were significantly associated with increased BMI levels. Subjects with even one component of the metabolic syndrome had a significantly higher risk for developing adenomatous polyps compared to those subjects without any component in Korean men.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Epidemiological evidence has shown that obesity is associated with an increased risk of mortality from cancers (1,2), and the metabolic syndrome has been considered a high-risk factor for certain types of cancer (3). Insulin resistance is linked to an increased risk of colorectal cancer mortality (4). In addition, hyperinsulinemia and metabolic abnormalities increase the risk for developing breast (5), prostate (6), and many other types of cancer (7,8).

The prevalence of obesity and the metabolic syndrome is rising dramatically in both developed and developing countries. According to Asia-Pacific criteria of obesity, defined as a BMI ≥25 kg/m2 (9), the prevalence of obesity in Korean has increased from 26.2% in 1998 to 31.8% in 2005 (10,11). Using the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (12), the prevalence of the metabolic syndrome in Korean men and women has been reported to be 14.2 and 17.7%, respectively (13).

Colorectal cancer is one of the most common malignancies in developed nations. South Korea has been changing rapidly due to globalization and westernization, and the incidence of colorectal cancer has increased rapidly such that it is now the fourth leading cause of cancer deaths in Korean men (14). The incidence of colorectal cancer has increased with the prevalence of obesity (15), due, at least in part, to changes in lifestyles and dietary patterns, as well as increased consumption of high calorie, high fat diets in Korea. Adenomatous polyps are considered precursors of colonic adenocarcinoma, and, being intermediate in the pathway to colon cancer, adenomatous polyps have been utilized to study risk factors associated with early stages of colonic neoplasia (16).

The incidence of colorectal cancer and adenomatous polyps may differ according to ethnic background. Although the incidence of colon cancer has increased steadily in Asian countries, it remains lower than that in Western countries. To date, however, there is insufficient information on the relationships of obesity and the metabolic syndrome with the presence of adenomatous colonic polyps in Asian countries. We therefore investigated the association between BMI and the metabolic syndrome with adenomatous polyps in Korean men.

Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Study population

We identified 3,932 healthy male subjects who visited the Health Promotion Center at Asan Medical Center, Seoul, South Korea, from January to December 2005 for routine health examinations and underwent colonoscopy. On the day of colonoscopy, anthropometric measurements were taken of each subject, and each answered a self-administered questionnaire and underwent a physical examination and blood tests. The self-administered questionnaire included questions regarding demographic, socioeconomic, and behavioral factors and medical history. Physical examinations were performed by physicians.

We excluded 247 individuals with missing anthropometric measurements and 560 individuals <40 or ≥70 years of age. We also excluded subjects with inflammatory bowel disease (n = 3), a history of polypectomy (n = 389), a history of cancer (n = 230), those in whom cancer was detected during this study (n = 59), those receiving anticoagulant therapy (n = 214), and those with hyperplastic polyps (n = 115) and inflammatory or nonspecific histological findings in pathology specimens (n = 217). Thus, the study population consisted of 1,898 subjects, 1,209 with normal colonoscopic examinations and 689 subjects with adenomatous polyps. Participants included 278 and 119 individuals who were receiving pharmacologic treatment for hypertension and diabetes, respectively. The study protocol was approved by the Institutional Review Board of Asan Medical Center.

Anthropometric measurements

Anthropometric measurements were made by well-trained examiners on individuals wearing light clothing and without shoes. Height was measured to the nearest 0.1 cm and weight to the nearest 0.1 kg using Inbody 3.0 (Biospace, Seoul, Korea); BMI was calculated by dividing weight (kg) by height squared (m2). Waist circumference was measured at the end of normal expiration to the nearest 0.1 cm, at the narrowest point between the lower border of the rib cage and the iliac crest.

Metabolic risk factors

A mercury sphygmomanometer was used to measure the blood pressure of each subject in the sitting position after a 10-min rest period. The appearance of the first sound (phase 1 Korotkoff sound) was used to define systolic blood pressure and the disappearance of the sound (phase 5 Korotkoff sound) was used to define diastolic blood pressure. Following an 8-h fast, blood was obtained from the antecubital vein of each subject into vacutainer tubes containing EDTA, and fasting plasma glucose, total cholesterol, triglycerides (TGs), and high-density lipoprotein cholesterol (HDL-C) were measured using an autoanalyzer (TBA-200FR; Toshiba, Tokyo, Japan).

Definition of metabolic syndrome

The metabolic syndrome was defined based on modified NCEP-ATP III criteria (17) and International Diabetes Federation (IDF) criteria (18). According to NCEP-ATP III criteria, subjects having three or more of the five following criteria were identified as having the metabolic syndrome: abdominal obesity, waist circumference ≥90 cm (19); systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg or current use of antihypertensive medication; fasting plasma glucose ≥100 mg/dl or current pharmacological treatment for diabetes; serum TGs ≥150 mg/dl; HDL-C <40 mg/dl. Adopting the IDF criteria, the metabolic syndrome was defined by central obesity (waist circumference ≥90 cm) plus two of the four metabolic risk factors detailed above.

Diagnosis of colonic polyps

Following careful bowel preparation with 4 l of polyethylene glycol-electrolyte oral lavage solution (Meditech Korea Pharma, Kyunggido, Korea), colonoscopy was performed on each subject by one of eight experienced gastroenterologists using an EVIS-260(B) colonoscope (Olympus, Tokyo, Japan), with the colon examined from the rectum to the cecum. All visualized lesions were biopsied and histologically assessed by experienced pathologists.

Statistical analysis

The χ2-test was used to compare differences in variables between subjects with normal colonoscopic findings and those with adenomatous polyps. The study subjects were divided into five groups according to the quintiles of BMI. The ranges of each quintile of BMI were <22.4, 22.4–23.7, 23.8–25.0, 25.1–26.6, >26.6 kg/m2. The relationships of BMI levels and the metabolic syndrome with the presence of adenomatous polyps were assessed by multiple logistic regression analysis, after adjustment for independent variables, including age, education, income, smoking, alcohol, exercise, medication, BMI, and waist circumference. Each odds ratio (OR) is presented together with its 95% confidence interval (CI). The linear trend in OR according to BMI levels and number of components of the metabolic syndrome was evaluated using the χ2-test for trend. All analyses were performed using SAS version 9.1 and were two-tailed. A P value <0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Demographic and clinical characteristics of subjects with normal and adenomatous colonic polyps are summarized in Table 1. Compared with subjects without polyps, those with polyps were older, had lower education or income levels, and smoked more, as well as having higher BMI, larger waist circumference, higher serum TG and lower HDL-C levels.

Table 1.  Demographic and clinical characteristics of subjects with normal colonoscopy results and adenomatous polyps
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Table 2 shows the associations of BMI levels and the metabolic syndrome with the presence of adenomatous polyps. After adjustment for all covariables, compared with men in the 1st quintile of the BMI, the ORs for adenomatous polyps in men in the 2nd, 3rd, 4th, and 5th quintiles of the BMI were 1.55 (1.10–2.19), 1.57 (1.10–2.24), 1.94 (1.34–2.81), and 1.99 (1.31–3.01), respectively (P for trend <0.0001). The adjusted OR for polyps was also significantly higher in men with TGs ≥150 mg/dl than in those with TGs <150 mg/dl (OR 1.29; 95% CI 1.03–1.62). The associations between the metabolic syndrome (NCEP-ATP III or IDF criteria) and adenomatous polyps were significant in the unadjusted analysis; however, these significances disappeared on multivariate analysis.

Table 2.  Odds ratio and 95% confidence intervals for adenomatous polyps relative to BMI levels and the metabolic syndrome
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Table 3 indicates the associations between numbers or clustering of components of the metabolic syndrome and adenomatous polyps. As a function of the number of metabolic risk factors, the ORs for adenomatous polyps were 1.41 (1.03–1.93), 1.52 (1.08–2.12), 1.46 (1.01–2.12), and 1.77 (1.08–2.90) for 1, 2, 3, and ≥4 risk factors, respectively (P for trend <0.05). Furthermore, relative to subjects without any component of the metabolic syndrome, the subjects with even one component had significantly higher OR for adenomatous colonic polyps.

Table 3.  Odds ratio and 95% confidence intervals for adenomatous polyps relative to number or clustering of components of the metabolic syndrome
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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES

Epidemiologic studies have shown that obesity is associated with a high risk for colon cancer (20,21), and that both obesity and abdominal obesity were associated with increased risk of adenomatous colonic polyps (22,23). Our study showed that the association between abdominal obesity and adenomatous polyps was significant in the unadjusted analysis, but these significances disappeared on multivariate analysis. However, we observed a significant association between BMI and polyps with a dose-response relationship. Compared with men in the 1st quintile of the BMI, the ORs for polyps were significant in men even in the 2nd quintile of BMI. Our results showed that cutoffs of the 2nd (22.4 kg/m2) and the 3rd (23.8 kg/m2) quintiles of the BMI were lower than the value for obesity defined as a BMI ≥25 kg/m2 according to Asia-Pacific criteria (9). Therefore, BMI might be the most sensitive anthropometric variable for predicting adenomatous colonic polyps in Korean men even within normal range of BMI.

The gene-encoding leptin has been linked to the growth and development of cancer (24). Leptin has been shown to regulate neoangiogenesis by itself and in concert with vascular endothelial growth factor and fibroblast growth factor 2. In addition to its proangiogenic activity, leptin can enhance endothelial cell growth and suppress apoptosis through a Bcl-2-dependent mechanism and can act as a mitogen, transforming or migration factor for many different cell types (25). In particular, leptin may be directly involved in colon tumorigenesis or it may serve as a sensitive and robust marker of an obesity-induced adverse endocrine environment (26,27).

Even the significance of associations between the metabolic syndrome (NCEP-ATP III or IDF criteria) and adenomatous polyps disappeared on multivariate analysis; however, significant associations between the presence of even one component of the metabolic syndrome and polyps, remained after adjustment. These findings may indicate that the presence of any components of the metabolic syndrome has a greater impact on the risk for the presence of adenomatous polyps rather than does a specific component of the metabolic syndrome. Our findings showed that clustering of components of the metabolic syndrome significantly increased risk for adenomatous polyps. Although the mechanisms linking these factors remain to be elucidated, the effects of clustering of metabolic risk factors on colorectal cancers might be mediated through insulin resistance or hyperinsulinemia (4). We also found that the risk of adenomatous polyps dose-dependently increased with the number of features of the metabolic syndrome. These findings are consistent with results showing that individuals with multiple features of the metabolic syndrome are more likely to be hyperinsulinemic or insulin resistant than individuals with only one feature of the metabolic syndrome (28).

In addition to these factors, the resulting dysregulation of the insulin-like growth factor axis has been shown to act as a growth factor and a mitogen during colonic carcinogenesis (29,30,31). Insulin resistance may lead to a compensatory increase in insulin secretion, and the resulting hyperinsulinemia may lead to increased levels of free insulin-like growth factor-1, a strongly antiapoptotic and mitogenic factor that decreases cell death and enhances cell growth (32). Moreover, insulin-like growth factor-1 is involved in the development, progression, and metastatic potential of cancers involving the colon, breast, prostate, and endometrium (33). Large prospective epidemiologic studies of biomarkers of insulin resistance have shown that individuals with higher levels of insulin are at higher risk for colon cancer (34).

Prospective studies have found that both men (35) and women (34) with diabetes were at increased risk of developing colorectal cancer. Similarly, a large cohort study in Korea found that serum glucose concentration was strongly associated with colon cancer (36). However, we did not observe a significant association between fasting plasma glucose and the presence of adenomatous polyps. In addition, we could not find significant associations between blood pressure or HDL-C and adenomatous polyps. The lack of associations between metabolic risk factors and adenomatous polyps may be due to a narrower range of values of metabolic variables, which could have been influenced by patient medications. As another consideration, the associations between the individual components of the metabolic syndrome and adenomatous polyps might differ according to the cutoffs of each component.

We found that high serum TG was significantly associated with adenomatous polyps, a finding in agreement with previous studies showing that lipid parameters related to insulin resistance were associated with adenomatous polyps (37). Serum TG concentration may be positively associated with bile acid synthesis and fecal bile acids. The increase of synthesized and secreted bile acids may provide abundant substrates for the formation of secondary bile acids and promote carcinogenesis in the large bowel (38). Lifestyle related to obesity is a well-established risk factor for adenomatous colonic polyps and colorectal cancer. We found that smoking was related to the presence of polyps, but alcohol consumption and physical inactivity were not. Previous studies have shown that smoking was associated with the metabolic syndrome (13) and insulin resistance (39), both of which are related to colon carcinogenesis.

This study had several limitations. There may have been a selection bias, in that subjects in this study were recruited from individuals who visited the hospital for regular health examination and underwent colonoscopies; thus, they were more concerned about their health status and were of a higher socioeconomic status than the general population. Approximately 32% of these individuals had colonic polyps, including hyperplastic polyps, an incidence slightly higher than in other studies in Asian countries (22,23). In addition, as this study was limited to men, we should speculate whether the results may be generalized to women.

The analysis is limited to only half (n = 1,989) of the original health subjects (n = 3,932). We excluded hyperplastic polyps and nonspecific histological findings which most series would include within normal colonoscopic findings as they present no increase in neoplastic risk. When we reanalyzed our data after those findings were included in the normal findings, we obtained similar results. A recent study reported that serum insulin levels are significantly correlated with the presence of not only adenomatous polyps but also hyperplastic polyps in the proximal colon (40). In this regard, we excluded hyperplastic polyps in the current study to reduce confounding factors.

There were some inadequate baseline data. We did not measure insulin or letin levels which seem to be linking mechanisms between obesity or the metabolic syndrome and adenomatous polyps. We also could not collect either the dietary data associated with colon cancer or each patient's precise medication history for treatment of hypertriglyceridemia or low HDL-C. Another limitation was that its cross-sectional design precludes a determination of causality. A prospective study is required to determine the causal relationship between obesity or the metabolic syndrome and adenomatous polyps or colorectal cancer in this population. However, our study design has strength as the control subjects were defined to have no polyps, as determined by the gold standard test.

The incidence of colon cancer and adenomatous polyps has increased as the prevalence of obesity and the metabolic syndrome has. In conclusion, adenomatous colonic polyps were significantly associated with increased BMI levels. Subjects with even one component of the metabolic syndrome had significantly higher risk for adenomatous polyps relative to subjects without any component in Korean men.

REFERENCES

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods and Procedures
  5. Results
  6. Discussion
  7. Disclosure
  8. REFERENCES