With the high incidence rate of CRC and very poor prognosis associated with the diagnosis, identification of potential chemopreventive agents is highly desirable. Previous studies showed that aspirin, NSAIDs and statins therapy may be associated with reduced risk of CRC. While insulin is a usually used medicine in the clinic, it is important to detect the effect of insulin use on the risk of CRC. In the present meta-analysis, we observed a significant 69% increased risk of CRC associated with insulin use by combining results from 12 epidemiologic studies, conducted in different populations, which were conducted to investigate the association between insulin use and risk of CRC. Nowadays, much has been known on the role of insulin use in cancer, several systematic reviews and meta-analysis, both on observational and interventional studies, have reported the harmful effect of insulin on cancer.
In our subgroup analyses, there are several interesting results. The subgroup analyses by the study designs showed that cohort studies alone showed no association between insulin use and risk of CRC. Although cohort study would avoid the selection bias and provide better evidence, in this study there were fewer cohorts included and it might be a possible perturbation of the results. Besides, the association of insulin use and risk of CRC in the cohort group was quite closed to the statistical significance level. So it is more reasonable to conclude that insulin use might be a risk of CRC. In the subgroup analyses by the sites, the result in Europe was different with the results from Asia and America. This might be explained by the geographical and ethnic differences. Besides, the environment, genetic factors and dietary factors differences might be possible causes. The stratified analyses by the gender showed that no association between both gender groups was detected. The reason of this outcome was that only 3 studies reported the data stratified by the genders. More well-designed studies are wanted for advanced research.
The potential biological mechanisms that relate insulin and CRC have been studied in several studies. There is evidence suggesting that diabetes is an independent risk factor for colorectal cancer; a meta-analysis showed an overall positive association . Insulin, which is usually used in patients with T2DM, might provide certain role in the increased risk of CRC; concurrently diabetes situation might be associated with the contribution of insulin on the increasing risk of CRC. Insulin and IGF-1 stimulate cellular proliferation; IGF-1 can inhibit apoptosis . Enhanced proliferation of mutated cells or failure to eliminate aberrant cells may contribute to colorectal carcinogenesis. We have previously shown that elevated insulin may contribute to the development of adenomas, the precursors to most colorectal cancer .
The strengths of this study include the comprehensive and systematic literature search of observational studies consistency of association between insulin and CRC, ability to evaluate the potential influence of measured confounders on the summary estimates. The likelihood of important selection or publication bias in our meta-analysis is small. During the identification and selection process, we did not exclude any article because of methodological characteristics. With the larger number of studies, we were able to carry out multiple subgroup analyses, evaluate heterogeneity and the presence of publication bias.
We aimed to conduct a rigorous meta-analysis; however, several limitations should be acknowledged. First, several of the included studies enrolled diabetic men from different ethnicities in the same geographic region. Our subgroup analysis was conducted according to region instead of ethnicity. Race has been reported to be one of the strongest risk factors for diabetes mellitus; however, since regional variation in diet is also a confounding factor for DM, we chose to consider location only. Secondly, we did not consider the associations between insulin use and CRC subtypes since there was limited data on this in the included studies, and it prevented classification of the subtypes. Finally, language bias was introduced, as our systematic review since our search included studies written in English only. This decision was based on the difficulty for us to retrieve all available literature in all languages.