2017 update on the relationship between diabetes and colorectal cancer: epidemiology, potential molecular mechanisms and therapeutic implications

Abstract

Worldwide deaths from diabetes mellitus (DM) and colorectal cancer increased by 90% and 57%, respectively, over the past 20 years. The risk of colorectal cancer was estimated to be 27% higher in patients with type 2 DM than in non-diabetic controls. However, there are potential confounders, information from lower income countries is scarce, across the globe there is no correlation between DM prevalence and colorectal cancer incidence and the association has evolved over time, suggesting the impact of additional environmental factors. The clinical relevance of these associations depends on understanding the mechanism involved. Although evidence is limited, insulin use has been associated with increased and metformin with decreased incidence of colorectal cancer. In addition, colorectal cancer shares some cellular and molecular pathways with diabetes target organ damage, exemplified by diabetic kidney disease. These include epithelial cell injury, activation of inflammation and Wnt/β-catenin pathways and iron homeostasis defects, among others. Indeed, some drugs have undergone clinical trials for both cancer and diabetic kidney disease. Genome-wide association studies have identified diabetes-associated genes (e.g. TCF7L2) that may also contribute to colorectal cancer. We review the epidemiological evidence, potential pathophysiological mechanisms and therapeutic implications of the association between DM and colorectal cancer. Further studies should clarify the worldwide association between DM and colorectal cancer, strengthen the biological plausibility of a cause-and-effect relationship through characterization of the molecular pathways involved, search for specific molecular signatures of colorectal cancer under diabetic conditions, and eventually explore DM-specific strategies to prevent or treat colorectal cancer.

Diabetes Mellitus and the Colon

“…Prospective studies and subsequent meta-analysis have suggested a strong link between DM and CRC (OR 1.27; 95% CI 1.21–1.34) [50–53]. It is widely believed that shared risk factors such as increasing age, obesity, high fat diet, sedentary lifestyle, and alcohol and tobacco use all play a role between diabetes and CRC [54–56].…”

“…A recent comprehensive review by González et al focused on potential therapeutics for specific molecular mechanisms that address both cancer and DM such as 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMGCoa) reductase inhibitors, renin-angiotensin-aldosterone system (RAAS) targeting (i.e., angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)), vitamin D receptor (VDR) activators, endothelin receptor antagonists such as atrasentan, anti-fibrotic agents such as anti-CTFG mAb FG3019 and anti-TGF-B1 mAb, anti-inflammatory agents such as chemokinetargeting agents and JAK/STAT inhibitors), epidermal growth factor inhibitors, and mTOR inhibitors [53]. …”

“…A systematic review of observational studies suggested that diabetic patients on metformin have a reduction in the rate of CRC compared to their diabetic counterpart not on metformin [53, 62–64]. Furthermore, a multicenter double-blind, randomized controlled phase III trial found that non-diabetic patients who received metformin 250 mg daily were less likely to have metachronous adenomas 1 year after polypectomy compared to those who received placebo (RR 0.67; 95% CI 0.47–0.97) [65].…”

“…Diabetics are 22% more likely to be up to date with their CRC screening; however, having DM is an independent risk factor for inadequate bowel preparation [53, 66–69]. This is most likely due to diabetics having slower gastric emptying and colonic transit [70].…”

Mediation of associations between adiposity and colorectal cancer risk by inflammatory and metabolic biomarkers

“…However, the biological mechanisms behind metabolism and CRC are complex, and may involve several pathways, such as energy sensing pathways (e.g. AMPK, Sirt1, and mTOR signaling) and the gut microbiome . Therefore, any mediation we observed does not necessarily identify C‐peptide, sOB‐R, and adiponectin as the causal agents driving associations between adiposity and CRC risk, but rather more likely represents the possible importance of metabolism and insulin response as key pathways linking adiposity with CRC risk.…”