Not all T2DM-related pathways contribute equally to CRC risk, and insulin resistance appears to be the dominant driver. This large genetic association study, published in Diabetologia, evaluated how distinct diabetogenic mechanisms contribute to CRC risk.

Individual-level data from 129,420 participants of European ancestry were analyzed, including 58,531 patients with CRC and 70,889 control participants from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. Eight validated partitioned polygenic scores (PPSs) were used to represent distinct diabetogenic processes, including relative insulin secretion insufficiency and insulin resistance with varying degrees of hyperinsulinaemia. Associations with overall and early-onset CRC were assessed using conditional logistic regression models.

PPSs reflecting insulin resistance-linked hyperinsulinaemia showed significant associations with CRC, particularly pathways related to lipodystrophy, body fat, and obesity (P < 0.001 for each). Compared with individuals in the lowest decile, those in the highest decile had higher odds of CRC, with odds ratios ranging from 1.09 to 1.15 across these pathways. In contrast, PPSs representing insulin secretion insufficiency or insulin resistance without hyperinsulinaemia showed no association with CRC.

The obesity-related hyperinsulinaemic insulin resistance PPS was also associated with increased odds of early-onset CRC, with the strongest effect observed among individuals with obesity (odds ratio 1.75; P < 0.001 for interaction with body mass index).

These findings indicate that insulin resistance-driven hyperinsulinaemia highlights the increased CRC risk associated with T2DM. Impaired insulin secretion does not appear to contribute to this association.