Plasma C-peptide, insulin-like growth factor-I, insulin-like growth factor binding proteins and risk of colorectal cancer in a nested case-control study: The Japan public health center-based prospective study†
Members of The Japan Public Health Center-based Prospective Study Group are: S. Tsugane, M. Inoue, T. Sobue, T. Hanaoka, National Cancer Center, Tokyo; J. Ogata, S. Baba, T. Mannami, A. Okayama, National Cardiovascular Center, Suita; K. Miyakawa, F. Saito, A. Koizumi, Y. Sano, I. Hashimoto, Iwate Prefectural Ninohe Public Health Center, Ninohe; Y. Miyajima, N. Suzuki, S. Nagasawa, Y. Furusugi, Akita Prefectural Yokote Public Health Center, Yokote; H. Sanada, Y. Hatayama, F. Kobayashi, H. Uchino, Y. Shirai, T. Kondo, R. Sasaki, Y. Watanabe, Y. Miyagawa, Nagano Prefectural Saku Public Health Center, Saku; Y. Kishimoto, E. Takara, T. Fukuyama, M. Kinjo, M. Irei, H. Sakiyama, Okinawa Prefectural Chubu Public Health Center, Okinawa; K. Imoto, H. Yazawa, T. Seo, A. Seiko, F. Ito, F. Shoji, Katsushika Public Health Center, Tokyo; A. Murata, K. Minato, K. Motegi, T. Fujieda, Ibaraki Prefectural Mito Public Health Center, Mito; K. Matsui, T. Abe, M. Katagiri, M. Suzuki, Niigata Prefectural Kashiwazaki and Nagaoka Public Health Center, Kashiwazaki and Nagaoka; M. Doi, A. Terao, Y. Ishikawa, Kochi Prefectural Chuo-higashi Public Health Center, Tosayamada; H. Sueta, H. Doi, M. Urata, N. Okamoto, F. Ide, Nagasaki Prefectural Kamigoto Public Health Center, Arikawa; H. Sakiyama, N. Onga, H. Takaesu, Okinawa Prefectural Miyako Public Health Center, Hirara; F. Horii, I. Asano, H. Yamaguchi, K. Aoki, S. Maruyama, M. Ichii, Osaka Prefectural Suita Public Health Center, Suita; S. Matsushima, S. Natsukawa, Saku General Hospital, Usuda; M. Akabane, Tokyo University of Agriculture, Tokyo; M. Konishi, K. Okada, Ehime University, Matsuyama; H. Iso, Y. Honda, Tsukuba University, Tsukuba; H. Sugimura, Hamamatsu University, Hamamatsu; Y. Tsubono, Tohoku University, Sendai; M. Kabuto, National Institute for Environmental Studies, Tsukuba; S. Tominaga, Aichi Cancer Center Research Institute, Nagoya; M. Iida, W. Ajiki, Osaka Medical Center for Cancer and Cardiovascular Disease, Osaka; S. Sato, Osaka Medical Center for Health Science and Promotion, Osaka; N. Yasuda, Kochi Medical School, Nankoku; S. Kono, Kyushu University, Fukuoka; K. Suzuki, Research Institute for Brain and Blood Vessels Akita, Akita; Y. Takashima, Kyorin University, Mitaka; E. Maruyama, Kobe University, Kobe; the late M. Yamaguchi, Y. Matsumura, S. Sasaki, S. Watanabe, National Institute of Health and Nutrition, Tokyo; and T. Kadoaki, Tokyo University, Tokyo.
The physical inactivity and obesity involved in hyperglycemia and hyperinsulinemia is supposed to lead to an increased bioavailability of insulin-like growth factor-I (IGF-I). The carcinogenic effect of IGF-I may be influenced by IGF binding proteins. We investigated the association between plasma levels of C-peptide, a surrogate biomarker of insulin, IGFBP-1, IGF-I or IGFBP-3, and the risk of colorectal cancer in a nested case-control study. During an 11.5-year follow-up, 375 newly diagnosed colorectal cancers were identified in a cohort of 38,373 adults who had returned the baseline questionnaire and provided blood samples. Two matched-controls for each case were selected from the cohort. The odds ratio (OR) of colorectal cancer for plasma levels of each protein was estimated using the conditional logistic regression model adjusted for potential confounding factors. We observed a statistically significant association of plasma C-peptide with colorectal cancer only in men. The ORs were 1.0, 2.3, 2.8 and 3.2 along with quartiles (p trend, 0.0072). The association was stronger in colon cancer (p trend, 0.025) than in rectal cancer (p trend, 0.24). Other peptides were not associated with the risk in either men or women. The results did not change when repeatedly analyzed by tumor invasion levels, tumor sites or follow-up periods. In conclusion, a higher plasma C-peptide may indicate a subsequent risk of colorectal cancer in Japanese men. © 2007 Wiley-Liss, Inc.
Physical inactivity and obesity are prominent risk factors for colorectal cancer.1 Hyperglycemia and hyperinsulinemia involved in these factors may underlie the biological mechanism of colorectal cancer development.2 Such elevated insulin suppresses the production of insulin-like growth factor binding protein (IGFBP)-1, which inhibits insulin-like growth factor (IGF)-I-stimulated cell growth and differentiation, leading to elevated IGF-I bioactivity.3 In addition, acromegalic population having an increased risk of colon cancer4 shows a high blood level of IGF-I, a growth-hormone-dependent peptide. The IGF-I is supposed to have a potent antiapoptotic and mitogenic properties in both normal and neoplastic cells.5 Growth hormone also increases insulin-like growth factor binding protein 3 (IGFBP-3), which has IGF-I-dependent and independent antiproliferative effects.3, 6 Both IGF-I and IGFBP-3 are circulating hormones and local paracrine factors with potential influences on cell growth.5, 6
Many nested case-control studies in prospective cohorts have been conducted on these peptides such as insulin7, 8, 9 or C-peptide,10, 11, 12 an indicator of an endogenous insulin secretion, IGF-I10, 12, 13, 14, 15, 16 and IGFBPs.8, 9, 10, 12, 13, 14, 15, 16 The evidence on C-peptide, which is better suited to assessing insulin secretion, is insufficient so far. Although the IGF-I findings have accumulated and are consistent, as meta-analyses showed,17, 18 those of IGFBP-3 are inconsistent.10, 12, 13, 14, 15, 16 There are few investigations regarding IGFBP-1 and their findings are inconsistent.9, 10, 12
We investigated the association between plasma levels of C-peptide, IGFBP-1, IGF-I or IGFBP-3 and the risk of colorectal cancer in a nested case-control study.
Material and methods
The Japan Public Health Center-based Prospective Study (JPHC study) is an ongoing cohort study investigating cancer, cardiovascular disease and other lifestyle-related diseases. The first group (Cohort I) of the JPHC study was started in 1990 and the second group (Cohort II) in 1993.19 Study subjects were mainly residents living in several municipalities in each area administered by a Public Health Center, regarding in age from 40 to 59 years in Cohort I and 40 to 69 years in Cohort II. Moreover, a sub-cohort of health check-up examinees was added to Cohort I, while 2 more sub-cohorts of examinees and random samples aged 40–69 from 1 city were added to Cohort II. The study subjects were identified by the population registry in each municipality. The sub-cohort of health check-up examinees in Cohort I mentioned earlier were excluded from this report, since their cancer incidence data were not available. Thus, we were left with a cohort of 65,803 men and 67,520 women. Our study was approved by the institutional review board of the National Cancer Center, Tokyo, Japan.
Using a self-administered questionnaire, study subjects were asked to provide information about their personal and familial medical histories, smoking, alcohol consumption, frequency of physical exercise, dietary habits and other lifestyle factors. Their dietary habits were assessed by a food-frequency questionnaire of 44 items for Cohort I20 and 52 items for Cohort II. A total of 50,456 men (77%) and 55,909 women (83%) filled out and returned the questionnaires.
Among the study subjects, 15,258 men (23%) and 26,703 women (40%) donated 10 ml samples of venous blood that was drawn into vacutainer tubes containing heparin. Samples were collected at the time of their health check-ups, which extended from 1990 to 1992 for Cohort I and 1993 to 1995 for Cohort II, and were divided into plasma and buffy layers, then preserved at −80°C until analysis. Of these blood samples, 57% were fasting samples (4 hr or more since last meal, Table I).
Table I. Baseline Characteristics of Cases and Controls
|N||196||392|| ||179||358|| |
|Age, years, mean||56.9||56.9||0.69||56.5||56.4||0.35|
|Smoking, pack-years, mean1||27.5||23.8||0.020||0.458||0.657||0.54|
|Alcohol consumption (g/week), ethanol, mean1||236||175||<0.0010||9.63||5.70||0.37|
|Body mass index2 (kg/m), mean1||23.8||23.2||0.027||23.5||23.6||0.68|
|Body height (cm), mean1||162.3||161.9||0.45||150.0||150.8||0.065|
|Physical exercise, n (%)2||49 (26)||75 (20)||0.12||33 (19)||54 (15)||0.28|
|Family history of colorectal cancer, n (%)||5 (2.6)||4 (1.0)||0.16||4 (2.2)||4 (1.1)||0.32|
|Past medical history of diabetes, n (%)||15 (7.7)||21 (5.4)||0.28||8 (4.5)||17 (4.8)||0.94|
|Vitamin supplement use, n (%)||35 (20)||53 (15)||0.11||24 (15)||54 (17)||0.43|
|Total energy intake (kcal/day), mean3||2,021||2,064||0.34||1,277||1,265||0.67|
|Dietary fiber intake (g/day), mean4||7.76||8.05||0.047||7.83||7.58||0.16|
|Folate intake (μg/day), mean4||328||329||0.60||298||291||0.31|
|Calcium intake (mg/day), mean4||441||463||0.15||452||423||0.074|
|Vitamin D intake (μg/day), mean4||6.58||6.67||0.54||5.57||5.16||0.047|
|Red meat intake (g/day), mean4||17.0||17.2||0.70||13.8||12.7||0.17|
|Fasting blood samples,5n (%)||110 (56)||219 (56)||0.90||103 (58)||204 (57)||0.79|
|Hormone use,6n (%)|| || || ||17 (9.5)||43 (12)||0.38|
|Postmenopausal diagnosis,7n (%)|| || || ||170 (95)|| || |
We followed study subjects until December 31, 2003. Those having died or moving to other municipalities were identified annually through residential registries in their Public Health Center areas. To confirm their causes of death, we used mortality data from the Ministry of Health, Labor and Welfare. Among study subjects, 9.9% had moved away, and 0.2% was lost to follow-up during the study period.
Selection of cases and controls
Incidence data on colorectal cancer were collected for the JPHC cancer registry through 2 data sources: local major hospitals and population-based cancer registries. Indicators of the completeness of colorectal cancer case-ascertainment conformed to the international standard21 as follows: information on 5.5% of incident cases first came by way of death certificates (Death Certificate Notification, DCN); 2.2% lacked any detailed information other than death certificates (Death Certificate Only, DCO); and 94.7% were verified by histological examination (Histological Verification, HV). We identified 375 cases (196 men and 179 women) of colorectal cancer up to December 31, 2003 from among the 38,373 subjects (14,004 men and 24,369 women) who had returned the baseline questionnaire, reported no diagnosis of any cancer and provided blood samples. All 375 cases were pathologically confirmed as adenocarcinoma, after excluding 18 cases of unknown pathology and 7 non-adenocarcinoma cases. Of these, 256 subjects had cancer of the colon [International Classification of Diseases for Oncology, Third edition (ICD-O-3)22 code C180 to C189] and 119 had cancer of the rectum (ICD-O-3 code C199 and C209). Colon cancers were classified into those of the proximal (ICD-O-3 code C180 to C185) or distal colon (ICD-O-3 code C186 and C187). Information on tumor depth was available in 370 of the 375 cases, with 120 tumors of the intramucosal type corresponding to Tis in the TNM classification,23 and 250 of the invasive type corresponding to T1 or more.
For each case, 2 controls were selected using incidence-density sampling24 from subjects who had no prior history of colorectal cancer when their case was diagnosed. Controls were matched for each case on sex, age (within 3 years), date of blood drawn (within 3 months), time since last meal (within 4 hr) and study location (Public Health Center area).
Plasma C-peptide was measured by radioimmunoassay using a reagent from Shionogi, Osaka, Japan. Plasma IGF-I was measured by immunoradiometric assay using a reagent from Mitsubishi Kagaku Iatron, Tokyo, Japan. This commercial assay measured total not bioavailable IGF-I. Plasma IGFBP-1 and IGFBP-3 were measured by immunoradiometric assay using a reagent from Diagnostic Systems Laboratories, Webster, TX. All analyses were assayed at Mitsubishi Kagaku Bio-Clinical Laboratories, Tokyo, Japan. Samples from matched sets were assayed together. All laboratory personnel were blinded with respect to case or control status. The intra-assay coefficients of variation from the quality control samples were 5.3% for C-peptide, 6.2% for IGFBP-1, 2.4% for IGF-I and 3.4% for IGFBP-3 (n = 20).
Adjusted means for cases and controls were calculated using least square means in an analysis of covariance by the PROC GLM procedure in SAS software (version 9.1; SAS Institute, Cary, NC). Percentages of baseline characteristics were unadjusted crude values. Baseline plasma levels of peptides were compared between cases and control using medians and interquartile ranges of each group because those levels were not normally distributed. We used extensions of the Mantel-Haenszel procedure25 with matched pairs for a comparison of the baseline characteristics and the baseline plasma levels of peptides between cases and controls, using the PROC FREQ procedure with the CMH option. Spearman correlation coefficients were calculated among plasma peptides and factors of body size and lifestyle. These coefficients were adjusted for sex, age and time elapsed since last meal at blood collection. The odds ratios (OR) and 95% confidence intervals (CI) for plasma levels of peptides divided into quartiles based on control distribution were calculated by a conditional logistic regression model adjusted for pack-years of smoking (continuous), alcohol consumption (continuous), body mass index (continuous), physical exercise (less than once a week, or once a week or more) and family history of colorectal cancer as well as by using matched pairs. The linear trend of OR was tested using the median values of IGF-I and IGFBP-3, or the logarithmic-transformed median values of C-peptide, IGFBP-1. p-values for the trend were evaluated using the 2-sided test with 0.05 as the significant level. We estimated the OR of cancer cases stratified by site or depth of tumor as well as the OR of all colorectal cancer cases. SAS software was used for all statistical analyses.
Pack-years of smoking or alcohol consumption were higher in cases than in matched controls in men but not in women (Table I). Other characteristics, including dietary factors, did not substantially differ between the 2 groups except for dietary fiber in men and vitamin D in women.
Plasma C-peptide was higher among cases than controls (Table II) in men but not in women. Except for C-peptide, there was no statistically significant difference between cases and controls in any peptides. Plasma levels correlated between C-peptide and IGFBP-1 [partial Spearman rank correlation coefficients adjusted for age and time since last meal (rs), −0.44 in men; −0.56 in women], and between IGF-I and IGFBP-3 (rs, 0.66 in men; 0.68 in women). A modest correlation was found between IGFBP-1 and body mass index (rs, −0.32 in men; −0.34 in women). Correlation coefficients were 0.19 in men and 0.24 in women between C-peptide and body mass index. Dietary factors were not correlated with plasma peptides. Those correlation coefficients were around 0.2 or less (see Supplementary Tables).
Table II. Baseline Concentrations of Plasma C-Peptide, Insulin-Like Growth Factor-I (IGF-I) and Insulin-Like Growth Factor Binding Proteins (IGFBP-1 and -3) between Cases and Controls
|C-peptide (ng/ml)||2.9 (1.8–4.9)||2.5 (1.5–4.5)||0.014||2.2 (1.5–3.8)||2.2 (1.6–3.8)||0.86|
| Fasting1||2.0 (1.5–2.8)||1.6 (1.2–2.5)||0.046||1.7 (1.2–2.7)||1.8 (1.3–2.4)||0.64|
| Nonfasting||4.9 (3.4–5.9)||4.3 (3.0–5.6)||0.14||3.5 (2.3–4.6)||3.4 (2.4–4.8)||0.78|
| Past medical history of diabetes||2.3 (1.6–2.8)||3.6 (2.2–5.1)||0.32||2.9 (1.9–3.3)||2.1 (1.8–3.2)||–2|
|IGFBP-1 (ng/ml)||16.4 (8.10–31.3)||19.3 (8.50–33.2)||0.29||14.2 (6.40–35.8)||16.4 (6.50–32.4)||0.66|
|IGF-I (ng/ml)||172 (137–206)||164 (136–204)||0.27||160 (129–190)||159 (121–197)||0.99|
|IGFBP-3 (ng/ml)||4,520 (3,995–5,170)||4,450 (3,895–5,050)||0.22||4,870 (4,320–5,490)||4,885 (4,260–5,440)||0.28|
Plasma C-peptide had a statistically significant association with colorectal cancer in men (Table III). The ORs were 2.3 (95% CI; 1.2, 4.5) for the second quartile, 2.8 (95% CI; 1.3, 6.1) for the third quartile and 3.2 (95% CI; 1.4, 7.6) for the highest quartile compared to the lowest (p trend, 0.0072). Other peptides were not associated with the risk of colorectal cancer. In women, there were no associations between plasma peptides and colorectal cancer.
Table III. Odds Ratio (OR) and 95% Confidence Interval (CI) of Colorectal Cancer for Baseline Concentrations of Plasma C-Peptide, Insulin-Like Growth Factor-I (IGF-I) and Insulin-Like Growth Factor Binding Proteins (IGFBP-1 and -3)
|OR1 (95% CI)||1.0 (reference)||2.3 (1.2–4.5)||2.8 (1.3–6.1)||3.2 (1.4–7.6)||1.0 (reference)||0.71 (0.39–1.3)||0.75 (0.40–1.4)||0.78 (0.38–1.6)|
|OR1 (95% CI)||1.0 (reference)||1.3 (0.74–2.3)||0.83 (0.41–1.7)||1.1 (0.52–2.5)||1.0 (reference)||1.1 (0.64–2.0)||0.56 (0.28–1.1)||1.1 (0.49–2.4)|
|OR2 (95% CI)||1.0 (reference)||0.70 (0.38–1.3)||0.78 (0.40–1.5)||0.83 (0.40–1.7)||1.0 (reference)||1.0 (0.57–1.8)||1.2 (0.59–2.2)||0.83 (0.38–1.8)|
|OR2 (95% CI)||1.0 (reference)||1.4 (0.74–2.5)||1.1 (0.58–2.2)||1.4 (0.65–2.8)||1.0 (reference)||1.1 (0.61–2.0)||0.88 (0.45–1.7)||1.1 (0.53–2.3)|
In addition, we examined ORs by tumor sites, i.e., colon or rectum (Table IV); by intramucosal or invasive type of tumor; or by the first follow-up period of less than 6 years or the last one of 6 years or more, conducted under a concept derived from some other studies.13, 15 The site-specific association of plasma C-peptide was stronger in colon cancer (p trend, 0.025) than in rectal cancer (p trend, 0.24). We also calculated subsite-specific ORs of proximal or distal colon cancer. The results seemed to show a stronger association in distal than in the proximal colon in men, although they were unstable. The OR estimates for cancers by tumor depth or follow-up period were not substantially different from those for all colorectal cancers (see Supplementary Tables).
Table IV. Odds Ratio (OR) and 95% Confidence Interval (CI) of Colon or Rectal Cancer for Baseline Concentrations of Plasma C-Peptide, Insulin-Like Growth Factor-I (IGF-I) and Insulin-Like Growth Factor Binding Proteins (IGFBP-1 and -3)
| C-peptide1||1.0 (reference)||2.1 (0.96–4.6)||2.6 (1.0–6.3)||3.5 (1.2–10)||0.025||1.0 (reference)||0.65 (0.29–1.4)||0.92 (0.41–2.0)||0.72 (0.28–1.8)||0.54|
| IGFBP-11||1.0 (reference)||1.5 (0.75–3.1)||1.3 (0.57–3.0)||1.6 (0.62–4.0)||0.47||1.0 (reference)||1.2 (0.57–2.5)||0.73 (0.31–1.7)||1.3 (0.47–3.5)||0.95|
| IGF-I2||1.0 (reference)||0.69 (0.33–1.4)||0.73 (0.33–1.6)||0.82 (0.36–1.9)||0.89||1.0 (reference)||0.99 (0.48–2.1)||1.1 (0.48–2.5)||0.64 (0.24–1.7)||0.43|
| IGFBP-32||1.0 (reference)||1.6 (0.74–3.3)||1.4 (0.64–3.1)||1.6 (0.67–3.7)||0.41||1.0 (reference)||1.3 (0.61–2.7)||0.88 (0.37–2.1)||1.4 (0.54–3.5)||0.52|
| C-peptide1||1.0 (reference)||1.8 (0.40–8.0)||3.8 (0.83–18)||2.2 (0.47–10)||0.24||1.0 (reference)||0.88 (0.34–2.3)||0.46 (0.14–1.5)||0.76 (0.23–2.5)||0.82|
| IGFBP-11||1.0 (reference)||0.86 (0.16–2.8)||0.21 (0.045–0.94)||0.30 (0.053–1.7)||0.056||1.0 (reference)||0.95 (0.37–2.5)||0.28 (0.075–1.1)||0.79 (0.21–2.9)||0.45|
| IGF-I2||1.0 (reference)||0.74 (0.20–2.8)||1.1 (0.25–5.1)||0.96 (0.16–5.7)||0.92||1.0 (reference)||1.1 (0.40–2.9)||1.4 (0.39–5.2)||1.4 (0.31–6.0)||0.75|
| IGFBP-32||1.0 (reference)||1.0 (0.31–3.4)||0.98 (0.21–4.7)||0.89 (0.19–4.2)||0.82||1.0 (reference)||0.83 (0.32–2.2)||0.67 (0.20–2.2)||0.77 (0.20–3.0)||0.73|
No further analyses show remarkable findings when compared with the results mentioned earlier. We did analyses with further adjustments for past medical history of diabetes in our multivariate-adjusted model. In addition, we limited analytic subjects to those without diabetes or those who provided fasting blood samples. We also conducted a further adjustment for hormone use history and an analysis limited to women diagnosed at postmenopause (aged 50 or more). Furthermore, we examined whether our multivariate-adjusted model was over-adjusted using a less adjusted model, i.e., a model not adjusted for body mass index and physical exercise. Moreover, a model not mutually adjusted for C-peptide and IGFBP-1, or IGF-I and IGFBP-3, was also examined. However, these efforts produced no substantial change in our results (see Supplementary Tables).
Plasma C-peptide, a biomarker indicating endogenous insulin secretion, was clearly associated with a subsequent risk of colorectal cancer in men. This result supported the finding that hyperinsulinemia caused by a high body mass index or low physical activity is involved in colorectal cancer development.1, 2, 3 Our study confirmed the previous reports showing association between hyperinsulinemia and colorectal cancer.7, 11 Nevertheless, it remains unclear why the association in our study was found only in men but not in women. Wei et al.12 examined this association in a nested case-control study derived from a US Nurses' cohort, where the association was positive but not statistically significant. However, Kaaks et al.10 reported a positive association between C-peptide and colorectal cancer in a nested case-control study of US women enrolled at a New York City mammography screening center. One possible explanation is that small or large variations of C-peptide concentrations may determine whether a statistically significant association is found between plasma C-peptide and the risk of colorectal cancer. A population showing a statistically significant association covered a wider range, 1.48–6.01 ng/ml (serum, unknown percentage of fasting subjects),10 than others showing a nonstatistically significant association, 0.9–3.6 ng/ml for the US Nurses' cohort (plasma, 60–70% of subjects were fasting),12 and 1.1–4.8 ng/ml for ours (plasma, 57% of subjects were fasting). The difference between serum and plasma samples is not a focus of argument, because plasma measurements highly correlate with serum ones, and there is no substantial difference between absolute values of plasma and serum measurements.26 Another possible reason may be the different characteristics of study populations as to whether obesity is detectable as a risk factor of colorectal cancer. The Nurses' Health Study27 and our cohort28 reported that a high body mass index was either weakly or not at all associated with the risk of colorectal cancer. In contrast, New York City women showed a strong association between body mass index and colorectal cancer.10 Moreover, we might interpret the factor of sex difference in the association between plasma C-peptide and colorectal cancer as follows: Considering findings that postmenopausal women may be protected from colorectal cancer by hormone replacement therapy,29 and that the body mass of postmenopausal women correlates with blood estrogen levels,30 women's adiposity might influence the risk of colorectal cancer differently when compared with men's adiposity in terms of increasing the risk.28 As another explanation, we expected to observe a statistical interaction between smoking or alcohol consumption and plasma C-peptide. In our cohort, male colorectal cancers were largely attributable to smoking and alcohol consumption, compared to female colorectal cancers.31 However, an additional analysis did not show such statistical interaction among them: Ps for interaction were 0.61 in men and 0.65 in women between smoking and C-peptide; and 0.52 in men and 0.64 in women between alcohol consumption and C-peptide.
IGFBP-1 was not associated with the risk of colorectal cancer. An elevated insulin level suppresses the production of this peptide,3 which also inhibits the IGF-I effect.6 Therefore, we hypothesized that IGFBP-1 is a protective marker against colorectal cancer. Some other studies showed an inverse association,10, 12 while another study did not.9 Since the evidence on this peptide has not yet been completely accumulated, further studies will be needed to confirm such an association.
IGF-I is consistently associated with the risk of colorectal cancer, especially in all but one15 previous studies.10, 12, 13, 14, 16 Our results were at odds with those reports. This discrepancy may be due to the difference in target populations. One previous study in Chinese men by Probst-Hensch et al.15 showed no association of IGF-I such as ours, both of which studies targeted Asian populations. Other studies showing a positive association were derived from Western populations. Still another explanation may be whether body height can be determined as a risk factor of colorectal cancer in a study population. From the viewpoint of the growth hormone-IGF-I axis, a tall body height resulting from a high secretion level of growth hormone has been associated with IGF-I exposure32 and the risk of colorectal cancer. Two studies from Western populations showed a positive association with the body height,33, 34 while our previous study did not, possibly because of a low percentage of taller adults.28 The growth hormone gene has a genetic polymorphism associated with a reduced secretion of growth hormone and IGF-I,32 and a reduced risk of colorectal neoplasms.35 However, the Japanese population did not seem to be associated with such a reduced risk in spite of a reduced secretion of IGF-I.35 IGF-I levels in our study covered a range similar to that of other Western10, 12, 13, 14, 16 and Asian populations.15 The association between the IGF-I level and the risk of colorectal cancer may differ among target populations, a difference that may be explained by the gene expression of IGF-I receptor making IGF-I effective. An animal study showed that colonocytic IGF-I receptor expression increased with an increased dietary lipid intake.36 A difference in dietary habits may lead to disparate levels of IGF-I receptor expression, resulting in different effects arising from the same blood IGF-I level.
IGFBP-3 is supposed to bind IGF-I and inhibit the IGF-I mediated-effect.3 In addition, anti-proliferative pathways involved in IGFBP-3 have been proposed.6 Although any actions of IGFBP-3 can be expected to reduce the risk of colorectal cancer, epidemiologic findings are not always consistent.17 Although US health professional cohorts have consistently found an inverse association between IGFBP-3 and colorectal cancer,12, 13, 14 other studies, including ours, reported that IGFBP-3 is not inversely associated with that risk.10, 15, 16 As Palmqvist et al.16 pointed out that it may be due to the fact that assay methods adopted differed between studies showing or not showing the inverse association. The US health professional studies used enzyme-linked immunosorbent assay (ELISA),12, 13, 14 while other studies used immunoradiometric assay10, 15, 16; however, Palmqvist et al.16 also reported that repeatedly assaying those same samples using ELISA did not substantially change the results, i.e., no inverse association of IGFBP-3.
We collected blood samples before cancer diagnosis, supporting the idea that plasma peptides indicated a cancer-free status and may predict a subsequent risk of colorectal cancer incidence. Plasma peptides were measured only once. Since plasma C-peptide is especially affected by time elapsed since the last meal, we matched that time interval between cases and controls to minimize the attenuation of risk estimates derived from measurement errors. Half-life of C-peptide in blood is very brief,37 while IGF-I and IGFBP blood levels are relatively stable.38, 39 We cannot entirely rule out a random misclassification of blood measurements as part of the reason for finding no association with the risk of colorectal cancer. Additionally, more outcomes may have been needed to exclude the risk of nonassociation by random variation or chance, especially when data stratified by sex or tumor site were analyzed.
In conclusion, a higher plasma C-peptide may indicate a subsequent risk of colorectal cancer in men. Our results did not support the existing hypotheses that IGF-I may increase and IGFBPs may decrease the risk of colorectal cancer.
We are grateful to all the staff members in each study area for their painstaking efforts in conducting the baseline and follow-up surveys. We are also indebted to the Iwate, Aomori, Ibaraki, Niigata, Osaka, Kochi, Nagasaki, and Okinawa cancer registries for providing their incidence data, as well as to Mr. Tomohiro Shintani, Mr. Hidehito Takenaka, and Ms. Kyoko Suzuki for their valuable technical assistance. Our sincere thanks also to Drs. Edward Giovannucci and Walter C. Willett for their helpful comments.