Is diabetes a causal agent for colorectal cancer? Pathophysiological and molecular mechanisms

Abstract

The possible relationship between diabetes mellitus (DM) and colorectal cancer (CRC), concerning pathophysiological and molecular mechanisms is highlighted in this review. The most recent and complete articles and developments in this particular field were thoroughly reviewed. Common risk factors, such as obesity, sedentary lifestyle, and Western diet between DM and CRC, led to the theory that DM might be a causal agent for CRC development. Various studies have connected type 2 DM and CRC, either proximal or distal, in both sexes. Additionally, chronic insulin treatment has been linked with increased colorectal tumor risk among type 2 diabetic patients. Interestingly, elevated hemoglobin A1c has been proven to be an independent predictor of aggressive clinical behavior in CRC patients. These mechanisms include the insulin-like growth factor-hyperinsulinemia theory and the participation of oncogenic intracellular signaling pathways. Furthermore, it has been proposed that Cox-2 inhibitors might have a role in decreasing the incidence of CRC. Finally, the use of statins to reduce the risk for colon cancer in patients with diabetes has remained controversial. Diabetic patients over 50 should receive counseling regarding their elevated risk for CRC, and screening colonoscopy should be recommended before initiating insulin therapy. However, there are no current guidelines, and this strategy is not yet applicable to some countries, as the corresponding risk would not allow screening colonoscopy to be adopted. There is strong evidence to indicate that DM is a causal agent for CRC development. This conclusion provides new impetus for re-evaluating CRC screening worldwide.

Keywords: Colorectal cancer; Diabetes mellitus; Molecular oncogenic pathways; Screening.

Figures

Figure 1

Schematic review of the molecular mechanisms linking diabetes mellitus and colorectal cancer. Insulin and insulin-like growth factor (IGF-1) signaling pathways are shown, along with their effect on apoptosis, proliferation, and protein synthesis. The activated mitogen activated protein kinases (MAPK) pathway is associated with proliferation and the phosphatidyl-inositol-3-kinase (PI3K)/protein kinase B (Akt) pathway mainly leads to survival (inhibition of apoptosis). Moreover, protein synthesis is induced via the Akt pathway. The complexity of the system and the cross-talk between the individual pathways are presented. MEK: Mitogen extracellular kinases; ERK: Extracellular signal-regulated kinases; mTOR: Mammalian target of rapamycin; Ras: “Rapid accelerating sarcoma” serine/threonine-kinase; Raf: “Rapid accelerating fibrosarcoma” serine/threonine-kinase; Ryk: Related to tyrosine kinases; SOS: Silencing of survival signals; Grb2: Growth factor receptor binding protein 2; APC: Activated protein C; GSK-3β: Glycogen synthetase kinase-3β; Axin: Activated extracellular index.