Serum C-Peptide, Insulin-Like Growth Factor (IGF)-I, IGF-Binding Proteins, and Colorectal Cancer Risk in Women
Rudolf Kaaks,
Paolo Toniolo,
Arslan Akhmedkhanov,
Annekatrin Lukanova,
Carine Biessy,
Henri Dechaud,
Sabina Rinaldi,
Anne Zeleniuch-Jacquotte,
Roy E. Shore,
Elio Riboli
Affiliations of authors: R. Kaaks, A. Lukanova, C. Biessy, S. Rinaldi, E. Riboli, International Agency for Research on Cancer, Lyon, France; P. Toniolo, A. Akhmedkhanov (Department of Obstetrics and Gynecology), A. Zeleniuch-Jacquotte, R. E. Shore (Department of Environmental Medicine), New York University School of Medicine, New York; H. Dechaud, Central Laboratory for Biochemistry, Hôpital de l'Antiquaille, Lyon.
Correspondence to: Rudolf Kaaks, Ph.D., International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France (e-mail: kaaks{at}iarc.fr).
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ABSTRACT
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Background: Leading a Western lifestyle, being overweight, and being sedentary are associated with an increased risk of colorectal cancer. Recent theories propose that the effects of these risk factors may be mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I. To test this hypothesis, we conducted a casecontrol study nested within a cohort of 14 275 women in New York. Methods: We used blood samples that had been obtained from these women from March 1985 through June 1991 and stored in a biorepository. C-peptide (a marker for insulin secretion), IGF-I, and IGF-binding proteins (IGFBPs)-1, -2, and -3 were assayed in the serum of 102 women who subsequently developed colorectal cancer and 200 matched control subjects. Logistic regression was used to relate cancer risk to these peptide levels, by adjustment for other risk factors. All statistical tests used are two-sided. Results: Colorectal cancer risk increased with increasing levels of C-peptide (Ptrend = .001), up to an odds ratio (OR) of 2.92 (95% confidence interval [CI] = 1.266.75) for the highest versus the lowest quintiles, after adjustment for smoking. For colon cancer alone (75 case subjects and 146 control subjects), ORs increased up to 3.96 (95% CI = 1.4910.50; Ptrend <.001) for the highest versus the lowest quintiles. A statistically significant decrease in colorectal cancer risk was observed for increasing levels of IGFBP-1 (Ptrend = .02; OR in the upper quintile = 0.48 [95% CI = 0.231.00]), as well as for the highest quintile of IGFBP-2 levels (Ptrend = .06; OR = 0.38 [95% CI = 0.150.94]). Colorectal cancer risk showed a modest but statistically nonsignificant positive association with levels of IGF-I and was statistically significantly increased for the highest quintile of IGFBP-3 (OR = 2.46 [95% CI = 1.095.57]). Conclusions: Chronically high levels of circulating insulin and IGFs associated with a Western lifestyle may increase colorectal cancer risk, possibly by decreasing IGFBP-1 and increasing the bioactivity of IGF-I.
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INTRODUCTION
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A Western lifestyle, typical of North America, Europe, or Australia, is associated with a high risk of colorectal cancer. Factors strongly related to such a lifestyle and, hence, implicated in colorectal carcinogenesis are a low level of physical activity and an energy-dense diet rich in fats and easily digestible carbohydrates. Physical inactivity and being overweighta consequence of a long-term positive energy balanceare associated with an increase in the risk of colon cancer, especially in men (1,2).
Most models have focused on exposures of the colonic mucosa to mutagenic or tumor-promoting compounds in the gut lumen derived from dietary components or formed in increased amounts within the large bowel. The traditional hypothesis is that a diet low in fat and high in fiber may protect against colorectal cancer by reducing intraluminal exposure to such toxic compounds (1,3). However, this hypothesis does not provide a direct explanation for the relationship between colorectal cancer risk and physical inactivity or being overweight. The hypothesis also does not explain observations that colorectal cancer risk may be related to the amount of intra-abdominal body fat, in particular (4,5).
A recent complementary theory proposes that a Western lifestyle may increase colorectal cancer risk by altering the metabolism of insulin and the bioactivity of insulin-like growth factors (IGFs) (2,6). Insulin and IGF-I regulate energy metabolism, stimulate cell proliferation and anabolic processes as a function of available energy and elementary substrates (e.g., amino acids), and inhibit apoptosis (2,79). Overeating, a lack of physical activity, and obesity cause insulin resistance and, hence, tend to increase plasma insulin concentrations. Insulin, in turn, can increase the bioactivity of IGF-I by inhibiting the synthesis of certain IGF-binding proteins (IGFBPs). On the other hand, plasma levels of both insulin and IGF-I are decreased by energy restriction (10,11), which in animal models protects against many forms of cancer (12,13).
Results from one prospective cohort study (14) showed an increased risk of colorectal cancer in men or women with elevated levels of plasma glucose during fasting or with elevated levels of plasma insulin 2 hours after a standard glucose load was administered. Another cohort study (15) recently showed an increased risk of colorectal cancer in men who had elevated levels of plasma IGF-I adjusted for levels of IGFBP-3.
In this article, we report findings from a casecontrol study nested in the New York University Women's Health Study (NYUWHS) cohort of 14 275 women, addressing the hypothesis that increased risk of colorectal cancer is associated with elevated prediagnostic serum levels of C-peptide [a marker for pancreatic insulin secretion (16,17)] or IGF-I and with decreased levels of serum IGFBP-1, -2, or -3, the three IGFBPs that vary most strongly with alterations in nutritional status and energy metabolism (10).
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SUBJECTS AND METHODS
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Study Design
The NYUWHS is a prospective cohort study that was designed primarily to address the role of endogenous hormones and diet in the etiology of cancer in women. From March 1985 through June 1991, 14 275 women aged 3565 years were enrolled at a mammography screening center in New York City. Eligibility was restricted to women who did not use any hormonal medication and who had not been pregnant in the 6 months preceding enrollment. More than 85% of the women stated that they were of Caucasian descent, and about 35% of the total eligible women stated that they were of Jewish origin.
Subjects were asked to complete a self-administered baseline questionnaire to collect demographic, medical, lifestyle, and reproductive information. The lifestyle questionnaire included questions about current smoking status (smoker versus nonsmoker) and diet and included a few questions about physical activity. In addition, all subjects reported their height and weight. Finally, all study subjects gave a 30-mL sample of venous blood that was drawn into collection tubes without anticoagulant. Cohort members returning to the clinic for renewed (annual) breast cancer screening were asked to donate additional blood specimens. With rare exceptions, blood collection took place between 9:30 AM and 1:00 PM. Subjects were not required to be fasting when blood was collected, but the exact time at venipuncture and the time since last consumption of any foods or drinks were recorded. After blood was collected, the tubes of blood were kept covered at room temperature (22 °C) for 15 minutes, stored at 4 °C for 60 minutes to allow clot retraction, and then centrifuged at 600g for 15 minutes at room temperature. Within 2 hours of centrifugation, 1-mL aliquots of the supernatant serum were distributed into capped plastic vials and stored at -80 °C.
The vital status and disease incidence of cohort members were ascertained to identify all women who developed malignant tumorsinvasive and noninvasiveafter cohort enrollment and to identify all subjects who died during the follow-up period. For follow-up until 1991, cohort members were contacted at the time of annual visits to the screening clinic or through mailed, self-administered questionnaires; for follow-up after 1991, active contact was by questionnaires mailed every 2 years and/or telephone calls. Subjects lost to follow-up were traced by contact persons, telephone directories, motor vehicle records, and a professional tracing agency. Telephone interviews were conducted by trained NYUWHS staff if a woman failed to respond to the mailed questionnaires. Active follow-up was completed with a passive follow-up through record linkages with the statewide tumor registries of New York, New Jersey, Connecticut, and Florida and with the U.S. National Death Index. Medical records were obtained from hospitals and were reviewed to confirm the pathologic diagnosis of cancer.
All subjects have given written informed consent to the use of their questionnaire data and blood samples for research purposes. The study was reviewed and approved annually by the Institutional Board Review Associates of New York University School of Medicine.
A total of 102 women received a diagnosis of colorectal cancer after their initial blood donation but before January 31, 1998, the last date of active follow-up. The median age at diagnosis was 64.4 years. The subsite distribution of 102 colorectal cancers thus identified was as follows: 25 in the right colon (appendix, caecum, ascending colon, and hepatic flexure), eight in the transverse colon, 31 in the left colon (splenic flexure, descending colon, and sigmoid colon), 11 at an unspecified location in the colon, 10 in the rectosigmoid junction, 13 in the rectum, and four at an unspecified location in the rectum. The time between blood donation and cancer diagnosis ranged from 0.2 to 9.4 years, with an average of 4.8 years. Of the 102 case subjects with colorectal cancer, 96 (94%) were diagnosed more than 1 year and 84 (82%) more than 2 years after the initial collection of blood. Control subjects were randomly selected from all cohort members alive and free of cancer at the time of diagnosis of the case subject and by matching the case subject with respect to menopausal status at enrollment (premenopausal or postmenopausal), age at recruitment into the cohort (±6 months), date of recruitment (±3 months), number of blood donations (visits to the screening center) over time, and time of day when blood was drawn (±1 hour). Two control subjects were selected for each case subject, with the exception of four case subjects for whom only one suitably matched control subject could be found, for a total of 200 control subjects. Subjects who used insulin to treat diabetes or who had malignant tumors at any location (except nonmelanoma skin cancer) before the date of diagnosis of the index colorectal cancer were not included in the study.
The concentrations of C-peptide, total IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3 were measured in a first serum sample for all study subjects. For 46 of the 102 casecontrol sets, the case subject and both control subjects had provided a second blood sample, after an average time interval of 1.33 years (range = 0.754.75 years) from first blood donation, and this second sample was also analyzed.
Samples pertaining to matched study subjects (i.e., sets of one case subject and two individually matched control subjects) were always analyzed on the same day with the same immunoassay kit. To control for the quality of each type of peptide measurement, analytical batches systematically included three standard serum samples and an unidentified aliquot of a pooled serum. The analyses were performed in two laboratories, one at the Hôpital de l'Antiquaille and the other at the International Agency for Research on Cancer, both located in Lyon, France. Laboratory personnel were blinded as to which serum samples were from case subjects with cancer or from control subjects. The level of C-peptide was measured by standard radioimmunoassay, and levels of IGF-I and IGFBP-1, -2, and -3 were measured by double-antibody, immunoradiometric assays. Reagents were from the following companies: for C-peptide, Cis-Bio (Gif-sur-Yvette, France); for IGF-I and IGFBP-3, Immunotech (Marseille, France); and for IGFBP-1 and IGFBP-2, Diagnostic Systems Laboratories (Webster, TX). Total IGF-I was measured after acidethanol precipitation of IGFBPs. The mean intrabatch coefficients of variation calculated from the quality-control samples in this study were 7.9%, 5.6%, 2.7%, 17.1%, and 2.6%, respectively, for C-peptide, IGF-I, IGFBP-1, IGFBP-2, and IGFBP-3.
Statistical Analyses
The reproducibility of the various peptide measurements between serum samples collected at the first and second visits was evaluated by calculating Spearman correlation coefficients. All additional statistical analyses were done on the mean of the peptide measurements from these visits when two serum samples were available and on the measurements for the first visit alone in the other subjects. Spearman correlations adjusted for age and casecontrol status were used to examine the cross-sectional relationships between the levels of serum C-peptide, IGF-I, and the IGFBPs and also the relationship between these peptides and height, weight, and body mass index (BMI = weight in kilograms/[height in meters]2).
A paired Student's t test was used to test for mean differences between anthropometric indices or hormone levels of case patients, and the average values for the two control subjects matched to each case subject. Univariate conditional logistic regression models were used to calculate odds ratios (ORs) for disease for quintile levels of C-peptide, IGF-I, and IGFBP-1, -2, and -3. Quintile cut points were determined on distributions of case and control subjects combined. Likelihood ratio tests were used to assess linear trends in ORs over the quintiles, scoring the five levels quantitatively as 1, 2, 3, 4, and 5. All statistical tests used were two-sided. We computed the 95% confidence intervals (CIs) by using the standard errors of the pertinent regression coefficients and by assuming a normal probability distribution for the estimated coefficients.
Multivariate logistic regression was used to estimate ORs adjusted for possible confounding factors other than those controlled for by matching. Depending on the models, these factors included smoking status at the time of blood donation and BMI. Associations of risk with levels of IGF-I were also estimated with adjustment for levels of each of the IGFBPs. These adjustments were made by a two-step procedure: First, in a multiple linear regression model, values of the peptide of interest were regressed on the potential confounding variables (smoking status, BMI, and IGFBPs), and quintiles were computed for the residuals of this regression analysis. Second, ORs were estimated for the quintiles of the residuals by multivariate logistic regression models. The same two-step procedure was also used to estimate ORs for each of the IGFBPs after adjustment for levels of IGF-I. When two serum samples were available for an individual, residuals were first calculated for each visit separately and then averaged. All logistic regression analyses were done with the PHREG procedure for proportional hazards regression in the Statistical Analysis System software package (SAS) (18). All statistical tests are two-sided.
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RESULTS
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Spearman rank correlations were moderate to high for measurements of levels of IGF-I (r = .87), IGFBP-2 (r = .76), and IGFBP-3 (r = .73) between the first and second visits. Likewise, high rank correlations were found for IGF-I levels adjusted for IGFBP-1 levels (r = .87), adjusted for IGFBP-2 levels (r = .86), or adjusted for IGFBP-3 levels (r = .82). Thus, for these measurements, a single serum measurement appeared to be highly representative of levels for at least 1 year. Correlation coefficients for levels of C-peptide (r = .62) and IGFBP-1 (r = .63) were somewhat lower.
Because measurements were made in blood samples obtained before any cancer diagnosis, case subjects and control subjects were combined for cross-sectional analyses (Table 1
). There was a strong positive correlation between IGF-I and IGFBP-3 (r = .51), the major IGFBP in blood. In addition, BMI correlated positively with serum C-peptide (r = .37), and both BMI and serum C-peptide correlated negatively with IGFBP-1 (r = -.50, for both) and IGFBP-2 (r = -.47 and -.33, respectively). None of the peptides showed any statistically significant correlation with height, and there were also no strong correlations between total IGF-I and IGFBP-1, IGFBP-2, or C-peptide. Smokers had statistically significantly higher levels of IGFBP-1 (27.15 ng/mL [95% CI = 23.7830.52] versus 20.81 ng/mL [95% CI = 18.1823.44]) and IGFBP-2 (583.4 ng/mL [95% CI = 511.6655.2] versus 508.9 ng/mL [95% CI = 455.4562.4]) than nonsmokers and had statistically significantly lower BMI (24.47 [95% CI = 23.7425.19] versus 26.02 [95% CI = 25.3026.74]) and C-peptide levels (0.84 pmol/mL [95% CI = 0.750.94] versus 0.89 pmol/mL [95% CI = 0.810.98]).
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Table 1. Cross-sectional correlations between C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins (IGFBPs), and anthropometric variables
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Case subjects had the same average height as control subjects but, on average, were heavier and had a statistically significantly higher BMI. The percentage of current smokers was also higher in the case subjects than in the control subjects (Table 2
), which confirms findings from another epidemiologic study (19). For smokers compared with nonsmokers, the OR was 2.09 (95% CI = 1.293.39).
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Table 2. Means and standard deviations of anthropometry indices, smoking status, and mean serum hormone measurements in case population with colorectal cancer and control subjects
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The mean serum concentrations of IGF-I, IGFBP-3, and IGFBP-1 were not statistically significantly different between case subjects and control subjects, but the mean concentrations of IGFBP-2 were lower in case subjects (573.8 ng/mL [95% CI = 519.1628.5] for control subjects versus 485.2 ng/mL [95% CI = 422.5548.0] for case subjects; P = .06) and the mean concentrations of C-peptide were higher in case subjects (0.84 pmol/mL [95% CI = 0.760.91] for control subjects versus 0.95 pmol/mL [95% CI = 0.861.05] for case subjects; P = .06) (Table 2
). After adjustment for smoking status, logistic regression analyses (Table 3
) showed weak, statistically nonsignificant increases in colorectal cancer risk with increasing levels of total IGF-I (Ptrend = .25) and IGFBP-3 (Ptrend = .19), with a statistically significant increase in risk only for the top quintile of IGFBP-3 (OR = 2.46; 95% CI = 1.095.57). A statistically significant increase in risk was observed, however, for increasing levels of C-peptide (Ptrend = .001), with an OR of 2.92 (95% CI = 1.266.75) for the top quintile versus the bottom quintile. When the analysis was restricted to colon cancer alone (75 case subjects and 146 control subjects), this trend for C-peptide was even stronger (Ptrend <.001), with an OR up to 3.96 (95% CI = 1.4910.50) for the top quintile. In addition to C-peptide, increasing levels of BMI were associated with statistically significant increases in the risk of colorectal cancer (Ptrend = .006) and of colon cancer alone (Ptrend = .01). The risk of colorectal cancer decreased statistically significantly with increasing serum levels of IGFBP-1 (OR = 0.48 [95% CI = 0.231.00]; Ptrend = .02) and for the highest quintile level of IGFBP-2 (OR = 0.38 [95% CI = 0.150.94]; Ptrend = .06).
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Table 3. Odds ratios (ORs) of cancer of the colorectum or of the colon for quintiles of serum insulin-like growth factor (IGF)-I, IGF-binding proteins (IGFBPs), C-peptide, and body mass index (BMI)*
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Adjusting the analysis further for BMI did not materially alter the associations of risk of colon or colorectal cancer with levels of IGF-I or IGFBP-3 but made the inverse associations with IGFBP-1 and IGFBP-2 levels practically disappear. The association with C-peptide level, on the other hand, did not decrease. (Estimated ORs actually became slightly stronger.) For colorectal cancer, the BMI-adjusted ORs with increasing levels of C-peptide were 1.00 (reference category), 2.26 (95% CI = 0.895.73), 2.61 (95% CI = 1.096.28), 2.68 (95% CI = 1.116.49), and 3.28 (95% CI = 1.308.26), with a Ptrend of .02. For colon cancer, these ORs were 1.00 (reference category), 1.98 (95% CI = 0.626.30), 3.89 (95% CI = 1.3111.55), 2.82 (95% CI = 0.918.68), and 4.89 (95% CI = 1.5915.04), with a Ptrend of .02. Conversely, the association of risk with BMI (adjusted for smoking) remained practically unaffected by further adjustments for C-peptide, IGFBP-1, IGFBP-2, or all three peptides combined. ORs for quintiles of BMI adjusted for C-peptide were 1.00 (reference category), 1.68 (95% CI = 0.684.14), 1.16 (95% CI = 0.462.90), 1.70 (95% CI = 0.664.38), and 3.43 (95% CI = 1.448.19), with a Ptrend of .02. Adjustment for IGFBP-3, the only IGFBP that was strongly correlated with IGF-I, did not substantially alter the observed relationships of colorectal cancer risk with IGF-I, and adjustment for IGF-I did not substantially alter the association of risk with IGFBP-3 (Table 4
).
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Table 4. Odds ratios (ORs) of cancer of the colorectum or of the colon for quintiles of serum insulin-like growth factor (IGF)-I and IGF- binding protein (IGFBP)-3, mutually adjusted*
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All of the findings above remained essentially the same when we excluded the data from the 18 case subjects with colorectal cancer whose diagnosis was made less than 2 years after the initial blood sample was collected and the data from their 28 matched control subjects.
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DISCUSSION
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In this prospective cohort study, we observed an increase in colorectal cancer risk with increasing serum concentrations of C-peptide. C-peptide is a marker for pancreatic insulin secretion that has a longer half-life than insulin itself and, therefore, reflects more accurately an individual's mean level of circulating insulin, especially when blood samples have not been systematically collected under fasting conditions (16,17). In addition to C-peptide, we found a statistically significant decrease in the risk of colorectal cancer with increasing levels of IGFBP-1 and with elevated levels of IGFBP-2. These results are concordant with those from another cohort study (14) that recently showed a positive association of colorectal cancer with serum insulin levels 2 hours after a standard glucose load was administered. For levels of total IGF-I, we observed only a very weak, positive association with risk, as was reported in another recent study within a cohort of U.S. male physicians (15). In contrast to the latter study, however, we observed no increase in colorectal cancer risk for elevated levels of IGF-I adjusted for IGFBP-3.
A major strength of our prospective study design is that blood samples were obtained before the clinical manifestation of the cancer. Thus, the observed casecontrol differences in serum hormone levels may be a cause but cannot be an effect of cancer treatment or the psychological stress and lifestyle changes after cancer diagnosis. The persistence of our results after exclusion of case subjects diagnosed in less than 2 years of the initial blood collection also makes it very unlikely that casecontrol differences were caused by a latent, as yet undiagnosed, tumor. Another advantage of the cohort-nested casecontrol design is that case subjects and control subjects are from the same, well-defined source population, which thus allowed us to avoid selection biases. In addition to its prospective design, our study incorporated measurements on a second blood sample from almost half of the study subjects. This component of our study showed remarkable stability over the time for the various peptides, which allows us to rule out lack of measurement reproducibility as a major explanation for the lack of strong associations especially of colorectal risk with levels of IGF-I, IGFBP-3, or IGF-I adjusted for IGFBP-3. The follow-up rate in the NYUWHS is very high, as illustrated by a capture/recapture analysis of incident breast cancers that confirmed that more than 95% of patients who developed cancer had indeed been identified by the standard follow-up procedures used for the study (20). This makes it unlikely that our results would be biased because case subjects with high levels of the risk factors measured would be more likely to be identified as a cancer case patient than the patients with low levels of the risk factor (or vice versa). Another form of bias that cannot be ruled out entirely, however, is lead-time bias (i.e., the possibility that screening advances the diagnosis of cancer). This type of bias would occur if high or low levels of risk factors measured were associated with an earlier detection of colorectal cancer cases because of a stronger tendency toward colorectal cancer screening.
Our findings that risk is positively associated with levels of serum C-peptide and inversely associated with levels of IGFBP-1 and IGFBP-2 fit with epidemiologic observations showing that being overweight, especially if the excess weight is in the abdominal area, is a risk factor for colorectal cancer (4,5). Furthermore, the slightly stronger association of levels of serum C-peptide with risk of colon cancer than with risk of cancers of the colon and rectum combined also fits observations that obesity and lack of physical activity are related to an increased risk particularly of colon cancer.
Being overweight and, particularly, having increased intra-abdominal body fat stores cause insulin resistance and, therefore, are associated with elevated fasting levels of insulin, as well with increased pancreatic insulin secretion after consumption of foods and drinks (21,22). Furthermore, insulin directly inhibits the synthesis of IGFBP-1 and -2 by the liver and other tissues (23,24) (Fig. 1
), and hyperinsulinemia is generally related to decreased plasma levels of both IGFBPs (2529). These physiologic interrelationships are reflected in our data, as shown by the positive associations of serum C-peptide levels with BMI and negative correlations of BMI and C-peptide levels with IGFBP-1 and IGFBP-2 levels.

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Fig. 1. Regulation of the bioactivity of insulin-like growth factor (IGF)-I by growth hormone (GH) and insulin. IGFBP = IGF-binding protein. Plus signs indicate a stimulating effect and minus signs indicate an inhibitory effect on synthesis and/or secretion.
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Even though being overweight was related to increased colorectal cancer risk, on the one hand, and to elevated C-peptide levels, on the other hand, risk remained positively associated with C-peptide after adjustment for BMI. Our results thus indicate that hyperinsulinemia may be a direct physiologic risk factor for colorectal cancer that is independent of BMI. This interpretation is supported by earlier observations of increased colorectal cancer mortality in subjects with high plasma glucose levels after an oral glucose challenge (30,31), which is a strong correlate of insulin resistance and of fasting and nonfasting blood insulin levels. It is also supported by observations of increased colorectal cancer risk in non-insulin-dependent diabetics who, although glucose intolerant, often also have increased blood insulin concentrations (3237). On the other hand, after adjustment for C-peptide, BMI remained associated with colorectal cancer risk and with levels of IGFBP-1 or IGFBP-2. The latter suggests that BMI may be a marker of hyperinsulinemia that is independent of C-peptide, possibly because measurements of C-peptide levels in only one or two (nonfasting) blood samples provides an imperfect index of an individual's long-term, average plasma insulin levels. An alternative interpretation is that not all of the impact of BMI on risk is mediated through alterations in these hormones.
For total IGF-I, our study findings concur with the results obtained in the Physicians' Health Study, in that increasing levels were related to mild, but statistically nonsignificant, increases in risk. In contrast to the Physicians' Health Study, however, our study showed an increase, not a decrease, in risk for the upper quintile of IGFBP-3. Consequently, IGF-I adjusted for IGFBP-3 was not related to any statistically significant increase in risk, in contrast again to the findings from the Physicians' Health Study, which showed a strong positive association between colorectal cancer risk and IGF-I levels, especially after IGF-I was adjusted for IGFBP-3. These differences between our study results and findings from the Physicians' Health Study occurred in spite of strong similarities in prospective study design, laboratory assays, and hormone measurement values. As in the Physicians' Health Study, we measured IGF-I and IGFBP-3 levels by double-antibody, immunometric assays, and the level of IGF-I was measured after acidethanol extraction to precipitate IGFBPs, a crucial step for the valid measurement of total IGF-I (38,39). The absolute levels for IGF-I and IGFBP-3 were very similar in the two studies: The 5th percentile, the mean, and the 95th percentile of the IGF-I measurements in our control group were 82, 181, and 284 ng/mL, respectively, compared with 111, 187, and 292 ng/mL in the Physicians' Health Study. Corresponding values for IGFBP-3 were 1870, 2935, and 3878 ng/mL, compared with 2023, 3066, and 4148 ng/mL, respectively. The slightly lower values for IGF-I and IGFBP-3 in our study could be explained by differences in sex (all of our study subjects were women, whereas all of the subjects in the Physicians' Health Study were men) or in age distribution (4042). The correlations between measurements of IGF-I and IGFBP-3 levels were also very similar between our study and the Physicians' Health Study (r = .54 versus r = .64, respectively, in the control groups).
The nutritional regulation of circulating levels of IGF-I and IGFBP-1, -2, and -3 is largely mediated along two axesone related primarily to growth hormone and the other to insulin (Fig. 1
). Growth hormone provides the key stimulus for synthesis of IGF-I and IGFBP-3 (7,10,11). Insulin, on the other hand, enhances the growth hormone-stimulated synthesis of IGF-I and IGFBP-3 by increasing the levels of growth hormone receptors (4345) and by stimulating cellular uptake of amino acids for protein synthesis (10,11). In addition, as mentioned earlier, insulin increases the bioactivity of IGF-I by inhibiting the synthesis of IGFBP-1 and -2. Prolonged fasting or malnutrition causes a state of growth hormone resistance, in which circulating levels of IGF-I and IGFBP-3 are strongly decreased, in spite of an increase in growth hormone secretion. This growth hormone resistance is related to a relative deficiency in endogenous insulin secretion and, hence, a decrease in the level of growth hormone receptors. In obesity, by contrast, plasma growth hormone is generally reduced (10,46), and this situation, in turn, often leads also to mild reductions in the levels of circulating IGF-I but not in the levels of IGFBP-3 (25,28). The obesity-related decrease in growth hormone secretion can, to a large extent, be explained by an increased negative feedback on pituitary growth hormone secretion by circulating free IGF-I [i.e., a small fraction of IGF-I unbound to IGFBPs (46,47) that increases when the concentrations of IGFBP-1 and -2 are decreased (25,28,29)].
From a cancer biology perspective, the hypotheses relating colorectal cancer risk to hyperinsulinemia and, hence, to reductions in IGFBP-1 and -2 levels (the hyperinsulinemia hypothesis) or to an increase in the levels of total circulating IGF-I, possibly reflecting increased pituitary growth hormone secretion (the growth hormone/IGF-I hypothesis), seem equally plausible. Both hypotheses are motivated by observations that IGF-I, and perhaps also insulin, can stimulate the proliferation and inhibit the apoptotic cell death of normal and neoplastic cells in vitro (7,8), including colonic mucosa epithelial cells (9,4850). Furthermore, increased IGF-I bioactivity in the colorectal mucosa might be related to increased levels of circulating IGF-I (either in total or relative to levels of IGFBP-3) or to reductions in the levels of circulating IGFBP-1 and -2 (7,8,10,51). The IGF-I/IGFBP system is extremely complex and involves endocrine, paracrine, and autocrine interactions between IGF-I, at least six identified IGFBPs, and cellular receptors. It is not entirely known how circulating levels of the growth hormone-dependent peptides IGF-I and IGFBP-3, on the one hand, and the insulin-dependent IGFBP-1 and -2, on the other hand, may be quantitatively related to IGF-I bioactivity in tissues.
From a nutritional endocrinology perspective, the hyperinsulinemia hypothesis appears to be most compatible with the observation that increased colorectal cancer risk is associated with being overweight or physically inactive. These two risk factors are associated with insulin resistance and hyperinsulinemia and, hence, with reductions in IGFBP-1 and IGFBP-2 levels. It is less clear which physiologic mechanisms could increase the level of total IGF-I, or of IGF-I relative to the level of IGFBP-3, in response to a Western diet and lifestyle.
In conclusion, this prospective study shows that elevated levels of C-peptidea marker of chronic hyperinsulinemia may increase colorectal cancer risk, possibly by decreasing the levels of serum IGFBP-1 and, hence, increasing the bioactivity of IGF-I.
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NOTES
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We thank Francine Claustrat, Béatrice Vozar, and David Achaintre for technical assistance with laboratory assays, Jennie Dehedin for secretarial assistance, and the three anonymous reviewers of this manuscript for constructive comments.
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Manuscript received December 27, 1999;
revised July 25, 2000;
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