We found little evidence that a diet with high insulin load or insulin index is related to colorectal cancer risk. Imprecise measurement of dietary insulin load and index could bias the results towards the null; however, the food insulin index, on which dietary insulin load and index were based, was developed under highly standardized conditions (14
): the insulin index value for each food represented the mean insulin responses of 11–13 subjects who consumed the test food on separate days. In a validation study, dietary insulin load has been shown to be an accurate measure of actual postprandial insulin responses (15
). Furthermore, in the NHS and HPFS, insulin scores was correlated with plasma triglycerides levels (a marker of insulin production), confirming that the estimation of dietary insulin load and index is able to predict an expected biological response (Dr. Katharina Nimptsch, personal communication).
The lack of association in the present study is consistent with most previous studies that examined glycemic load and glycemic index in relation to colorectal cancer. A recent meta-analysis of studies up to 2008 showed that the pooled RRs of colorectal cancer were 1.06 (95% CI=0.95–1.17; n=8 cohort studies) for glycemic load and 1.04 (95% CI=0.92–1.12; n=7 cohort studies) for glycemic index (13
). In contrast, high blood insulin levels have been associated with increased risk of colorectal cancer in a number of serologic studies (5
). A recent meta-analysis which summarized epidemiological studies up to 2007 (24
) showed that the pooled RR of colorectal cancer was 1.35 (95% CI=1.13–1.61; n=10 prospective studies and 1 case-control study) comparing the highest versus lowest category of insulin or C-peptide.
One explanation for the disparate findings with serum insulin and insulinogenic diets is that long-term insulin levels may not be greatly influenced by the consumption of insulinogenic foods, because food intake increases postprandial insulin demand and therefore affects insulin levels only temporarily (2
). As insulin resistance greatly upregulates the long-term secretory tone and causes a compensatory increase in both basal insulin secretion and postload insulin responses, it is possible that insulin resistance, instead of insulinogenic food intake, is the primary contributor to the sustained hyperinsulinemia that is relevant to cancer development. In the prospective Northern Sweden Health and Disease Cohort, fasting insulin (which mainly reflects the degree of insulin resistance) was positively associated with colorectal cancer and no association was observed for a mix of fasting and nonfasting samples (which reflects both insulin resistance and the influence of insulinogenic foods) (7
); in a subcohort of that study, C-peptide levels were positively associated with colorectal cancer risk among fasting women but not among nonfasting women (25
). Several other studies found similar increased risk of colorectal cancer for both fasting C-peptide and a mix of fasting and nonfasting C-peptide (8
); observed positive association with postprandial hyperinsulinemia may principally be due to underlying insulin resistance as well. These findings and our results suggest that high intake of insulinogenic foods alone might not be enough to induce sustained hyperinsulinemia and therefore less likely to influence colorectal cancer risk.
The insulin scores have limitations. They were developed to assess total quantity of insulinogenic food intake, but were not designed to measure meal frequency and food combinations which might also affect insulin response. Another concern is that the food insulin index values were derived from lean university students (14
) whose absolute insulin response is likely to be different from that of the older and heavier subjects; however, the method is valid if the increase in insulin levels induced by a food, i.e., the relative insulin response, is comparable between the two groups. Actually, in the biomarker validation study (Dr. Katharina Nimptsch, personal communication), we observed that the positive association between the insulin index and triglycerides was much stronger among overweight individuals, indicating that the general method used to develop the insulin index works among heavier subjects.
In summary, our data suggest that high intake of foods that increase postprandial insulin levels may not play a major part in colorectal cancer development. Further studies should focus on the role of insulin resistance to provide a more precise and thorough understanding of the insulin-colorectal cancer hypothesis.