Narrative review of the influence of diabetes mellitus and hyperglycemia on colorectal cancer risk and oncological outcomes

Diabetes mellitus (DM) and hyperglycemia have been shown to have significant effects on the incidence, chemore-sistance, and prognosis of colorectal cancer (CRC), as well as the outcomes of localized and metastatic CRC. In-flammation and endocrine effects may act as central mechanisms of DM and cancer and stimulate the insulin -like growth factor 1-phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (IGF-1-PI3K-AKT-mTOR) path-way. Dysregulation of the AMP-activated protein kinase (AMPK) pathway leads to metabolic imbalance and in-dicates cancer risk. The use of metformin for chemoprevention has been shown to reduce CRC and adenoma incidence through the upregulation of AMPK, which causes cell cycle arrest in the Gap 1-S (G1-S) phase and in-hibits the mTOR pathway, even potentially reversing the epithelial-mesenchymal transition. However, evidence of the effects of metformin remain controversial in cancer prognosis. Several genes, such as transcription factor 7-like 2(TCF7L2), tumor protein P53 inducible nuclear protein 1(TP53INP1), gremlin 1 (GREM1), and potassium voltage-gated channel subfamily Q member 1(KCNQ1), are pleiotropically related to DM as well as cancer risk and prognosis. Epigenetic modification of members of the Let-7 family such as miR-497, miR-486, and miR-223 is strongly associated with impaired glucose tolerance and CRC risk. Herein we review the pathophysiological and epidemiological evidence as well as potential underlying molecular mechanisms by which DM and hyper-glycemia affect CRC risk. We also suggest potential roles of glucose modulation in CRC therapy and propose an agenda for future research and clinical practice.

Automated summary

Diabetes mellitus and hyperglycemia significantly affect the incidence, chemoresistance, and prognosis of colorectal cancer through inflammation, endocrine effects, and metabolic imbalance. Metformin shows potential as a chemopreventive agent, but its effects on cancer prognosis remain controversial. Genetic factors and epigenetic modifications also play a role in the relationship between diabetes, colorectal cancer risk, and prognosis.