Type 2 diabetes mellitus and risk of colorectal adenoma: a meta-analysis of observational studies

Diabetes mellitus (DM) is the fourth or fifth leading cause of death in developed countries and one of the biggest threats to human health worldwide [1]. More than 90 % of all DM is type 2 diabetes mellitus (T2DM) [2, 3]. Colorectal cancer (CRC) is the third most common cancer in the world. Colorectal adenoma (CRA) (also known as adenomatous polyp and always found by colonoscopy screen [4]) is a prevalent precancerous lesion that can lead to CRC through the adenoma–carcinoma sequence [5].

Research on risk factors for CRA has focused on several epidemiological factors, including smoking [6], alcohol consumption [5], body mass index [7], physical activity [8], and calcium intake [9]. Recent research on patients with diabetes suggested that insulin therapy and diabetes itself may increase the risk of CRC [10‐12]. However, the association between T2DM and the risk of CRA risk has not yet been fully established. Some researchers asserted that there were no overall associations between T2DM and CRA risk [13‐16], while others reported a higher risk [17‐20]. To further examine these findings and provide evidence of association between T2DM and risk of CRA risk, we performed a meta-analysis about T2DM on the risk of CRA.

This study indicated that patients with diabetes, especially type 2, have about 50 % increased relative risk of developing CRA than non-diabetic individuals, regardless of their geographic location. Although sample size was small in the newly diagnosed T2DM subgroup, the heterogeneity was also small and a significant risk relationship between T2DM and CRA was still detected. A similar result was only found in the advanced adenoma subgroup, not in the proximal, distal, colon or multiple adenoma subgroups. When low-quality studies were excluded, the positive association still existed. These results suggested that T2DM patients should pay more attention to their risk of CRA.

The positive relationship between T2DM and CRA may be linked to insulin resistance or an increased insulin-like growth factor 1 (IGF-1) might take effect in the adenoma–carcinoma process. High insulin levels could promote tumor growth [31, 45, 46]. Also, diabetes may lead to slower bowel transit, which would increase the probability of exposure to potential carcinogens for colonic mucosa [47‐49]. It is worth noting that there might be some confounding effects because of the similar risk factors for both T2DM and CRA, such as physical inactivity, obesity, and an unhealthy diet habit [12, 50]. For example, a case–control study reported that higher red meat intake could significantly increase the risk of colon adenoma [51]. At the same time, obese people also tend to consume more red meats and have a higher risk of diabetes. Therefore, dietary habits might be a confounding factors. Finally, some researchers also report that obesity might be a confounder in the association between T2DM and colorectal disease [52].

Some studies reported a difference in risk between males and females [12, 39, 53‐55]; however, the results of our subgroup analysis showed no difference. One possible explanation involves the redistribution of body fat that can occur when women experience menopause. The increase in visceral body mass fat could lead to hyperinsulinemia so that women, especially post-menopausal women, are more susceptible to colorectal diseases. However, the existence of menopause in some women cannot explain the different CRC risks for males and females [56‐59]. Discrepancies among these studies and ours and the insignificant results by adenoma sub-site might be attributed to the limited sample sizes and insufficient statistical power. For the prospective studies, varied different follow-up procedures and mix of ethnicities different study populations might be the sources of heterogeneity.

Our analysis revealed that with T2DM have about a 5 % higher risk of CRA than newly diagnosed diabetes patients, revealing the duration of T2DM as a risk factor for CRA. A possible explanation is that known T2DM patients’ bowels are exposed to hyperinsulinemia or a hyperglycemic environment for a longer time, and such hormonal or metabolic abnormalities (according to former study [60]) could affect tumour growth. However, some studies reported that metformin use was a protective factor of CRA [33] and cancer [61]. If this is true, diagnosed diabetes patients should have a lower risk of adenomas than new patients, which is counter to our results. On the other hand, the severity of T2DM, which was not confirmed in the included studies, may affect colorectal disease risk and contribute to the mixed results. In sum, there might be a dose–response relationship between insulin and CRA, and further studies should include this as an important potential confounding factor.

Several limitations of in this meta-analysis that should be taken into consideration. First, results for several subgroups, such as gender and adenoma sub-site subgroup, were based on a limited number of studies. Therefore, we cannot rule out the possibility that insufficient statistical power is present. Second, in the present analysis, some small studies with inverse associations between T2DM and risk of CRA risk seemed to be suppressed. The presence of possible publication bias could have led to an overestimation of the effect of T2DM on CRA risk. However, the adjusted result was comparable after trim and fill method corrections. Third, we could not account for all of the confounding factors in the meta-analysis, though most confounders were adjusted in the original RRs. Many factors might induce the adenomas, such as age, ethnicity, inactivity, regular aspirin use, obesity, and family history of CRA, and menopausal status. We could not control for these covariates because of lack of relevant data. Relevant studies with additional data on these other factors may be found by searching by searching beyond the sources used for this study. Furthermore, we could not determine whether using insulin as a therapy for T2DM is an important factor because CRA risk might be altered by hyperinsulinemia, thought to be an important promoter of carcinogenesis [62, 63]. At the same time, metformin may have a direct anti-proliferative effect [64]. Finally, most of the existing studies did not discuss the influences of T2DM severity level on CRA risk. Thus, more cohort studies about these topics should be conducted.

In conclusion, the results of our meta-analysis indicated that patients with T2DM have higher risks for the development of CRA, which is an important inducement for colorectal cancer. Our study has important implications for clinical and public health. Because T2DM and CRA are prevalent in the developed and developing countries [65], medical workers should increase the rate of CRA screening for T2DM patients so that they can benefit from behavioural interventions that can help prevent CRA [38]. Large prospective studies that investigate the interactions among environmental and behavioral factors, medications, and functional polymorphisms are also needed to further clarify the etiology of CRA.