In this study, we evaluated the relationship between insulin, C-peptide and IGFBP-1 in relation to colorectal adenomas and low apoptosis. We found that elevated levels of insulin and C-peptide predicted increased risk of adenomas in men and women, while elevated levels of IGFBP-1 reduced risk, particularly in men. The risk of adenomas increased with increasing concentrations of C-peptide and insulin, and decreased with increasing concentrations of IGFBP-1. We also found that in overweight and obese individuals higher C-peptide increased the risk of low apoptosis, particularly in men, whereas elevated IGFBP-1 levels were associated with a reduced risk of low apoptosis, an association that was stronger in men. These findings suggest that the mechanism by which these hormones increase risk of adenomas may reflect their anti-apoptotic properties.
Insulin is secreted as pro-insulin and subsequently cleaved into insulin and C-peptide. C-peptide is a marker of pancreatic insulin synthesis, and several epidemiologic studies have utilized C-peptide as an alternate biomarker to insulin because it has a longer half-life than insulin and therefore is more stable [28
]. We found positive associations between insulin, C-peptide and adenomas, in both men and women. While these findings contrast with those by Yamaji et al., who found these associations only in men in a Japanese cohort [24
], they confirm both our previous observations in an independent patient population [17
], and in a recent report in which we found race/ethnicity differences for genes related to the IGF axis [29
]. The observed positive association between insulin, C-peptide and adenomas not only highlights the importance of the insulin-IGF pathway in risk of colorectal adenomas and cancer, but it also supports findings from previous studies [19
]. Higher IGFBP-1 levels were associated with a reduced risk of adenomas. In these analyses, we did not observe significant differences between cases and controls for IGF-I; these findings are consistent with the hypothesis that higher levels of insulin and C-peptide, and lower levels of IGFBP-1 are the trigger points early in the disease development. Overall, these findings are in agreement with those of others [22
], and support the hypothesis that biologically available IGF-1 circulating levels may be an etiologic factor in the formation of adenomas.
Only a limited number of studies have evaluated IGFBP-1 in relation to adenomas or cancer [22
] but the results are inconsistent [19
]. IGFBP-1, a member of the IGF binding protein family binds to IGF-I or IGF-II to regulate their bioavailability, in this way acting as a modulator of cellular proliferation and cell death [35
]. IGFBP-1 can also inhibit metabolism of IGFs [36
], and IGFBP-1 expression is negatively regulated by insulin [37
]. Levels of circulating C-peptide and insulin inversely correlate with plasma IGFBP-1 levels [14
], thus our findings support this observation. They however contrast with a recent report [32
] in which high IGFBP-1 levels were inversely associated with colorectal cancer in women, since we only observed statistically significant associations in men. In a larger cohort, Le Marchand et al. also observed a significantly reduced adenoma risk with higher plasma IGFBP-1 levels [22
]. Yamaji et al. reported similar associations in Japanese men [24
]. Our first attempt to test for IGFBP-1 associations with low apoptosis, showed that overweight and obese individuals with higher C-peptide levels are more likely to have low apoptosis.
Epidemiologic studies suggest that lifestyle and dietary factors play an important role in the etiology of colorectal cancer. In particular, obesity is associated with increased risk of colon cancer, especially in men [38
]. Men are also more likely to have higher waist-hip ratio, a condition that is associated with elevated levels of insulin and C-peptide [40
]. Our findings show strong positive correlations between insulin or C-peptide and BMI or WHR among both men and women. In addition, there was a strong inverse association between IGFBP-1 and BMI or WHR. These findings suggest that metabolic characteristics associated with obesity and visceral adiposity may be important biomarkers of adenoma risk.
The major strengths of this study include availability of fasting blood specimens, detailed information on exposures and anthropometrics and ability to measure apoptosis in normal mucosal biopsies and test for correlations with circulating insulin, C-peptide or IGFBP-1 levels. There are some limitations of this study. Plasma samples were only available for one-time measures of insulin, C-peptide and IGFBP-1. However our findings are similar to other studies that used one-time measures of these analytes. Also, future studies should consider measuring insulin resistance based on the Homeostatic Model Assessment (HOMA).
In summary, we found significantly elevated levels of insulin and C-peptide in patients with adenoma when compared to adenoma-free controls. Elevated concentrations of IGFBP-1 reduced the risk for adenomas in men. These findings confirm our previous observations in an independent patient population and support the involvement of the insulin-IGF pathway in the etiology of colorectal carcinogenesis. Elevated C-peptide and insulin significantly predicted adenoma risk although C-peptide appeared a stronger predictor of low apoptosis in overweight and obese men than women. The strong positive association between BMI and WHR, known colorectal cancer risk factors that are also related to hyperinsulinemia and the insulin-IGF axis, suggests an interplay between obesity, insulin-related factors and adenomas. Our findings suggest that the anti-apoptotic properties of these peptide hormones, particularly C-peptide, may be the primary driver of associations with adenomas. Preventive measures to reduce obesity and closer monitoring of individuals may be beneficial to reducing adenoma and cancer risk.