High concentration of sugars is genotoxic to folate-deficient cells

Patients with type 2 diabetes mellitus (T2DM) are associated with an elevated, but poorly understood baseline of genomic instability (GIN). Expert panels are still debating on whether hyperglycemia is the key element in conferring this high GIN. Since high blood glucose and low blood folate are prevalent in T2DM, we hypothesized that high glucose may work with low folate to induce GIN. Using NCM460, CCD841 and L02 cell lines as in vitro cell models, we investigated the genotoxic effects of high sugars (HS; 1-2% glucose, fructose, galactose or sucrose) alone or in combination with folate deficiency (23 nM, FD) over a course of 7 days by the cytokinesis block micronucleus assay. We found that HS is nongenotoxic to NCM460, CCD841 and L02 cells. However, the combination of HS and FD induced significantly higher levels of micronuclei, nucleoplasmic bridges and nuclear buds. Our in vitro work demonstrates that HS is non-genotoxic under folate repletive condition, but is genotoxic under FD condition. These results provide preclinal proof of concept that concomitant hyperglycemia and low folate may explain, at least in part, the high baseline of GIN in T2DM patients, suggesting that folate levels should be kept under control in order to limit the risk of GIN and carcinogenesis in T2DM.