Objective  To investigate the molecular mechanism by which U2 snRNP-associated SURP domain containing protein (U2SURP) influences the proliferation of HCT116 colorectal cancer cells under high glucose conditions, and to examine the effect of metformin. Methods  Clinical samples from colorectal cancer (CC, n=8) and diabetes-CC(DCC, n=8)patients were collected. High-glucose cell model was established by culturing HCT116 cells with 33 mmol/L glucose for 8 days. Diabetic xenograft model was generated by inducing diabetes in C57BL/6 mice via streptozotocin (STZ) injection (120 mg/kg) and subsequent subcutaneous implantation of MC38 cells. U2SURP expression in tissues and cells were analyzed by Western blotting and Real-time PCR. The proliferation level of HCT116 cells was analyzed by CCK-8 and colony formation assays following U2SURP knockdown using short hairpin RNA(shRNA) and cell cycle progression was analyzed by flow cytometry. The upstream regulator of U2SURP was predicted by the SRAMP and RBP suite databases. The expression level of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) was examined in diabetic mouse xenograft models and high glucose-cultured cell models. Overexpression and knockdown cell lines were constructed to validate their effects on the proliferation of colon cancer cells under high glucose conditions. Using the high-glucose cultured HCT116 cell model, treatment with metformin (0.0128 mol/L), detected the expression of U2SURP and its upstream factor, cell proliferation capacity, and analyzed the regulatory role of the Akt/glycogen synthase kinase-3 (GSK-3β) signaling pathway. Results  U2SURP expression was significantly upregulated in both diabetic colorectal cancer tissues and high glucose-cultured HCT116 cells. High glucose promoted colorectal cancer cell proliferation, whereas knockdown of U2SURP inhibited this pro-proliferative effect and induced S-phase cell cycle arrest. We next screened IGF2BP3 as an upstream regulator of U2SURP and confirmedits overexpression promoted the proliferation of colon cancer cells, while its knockdown reversed the pro-proliferative effect of high glucose. Furthermore, metformin inhibited the upregulation of U2SURP and IGF2BP3 under high glucose conditions, weakened cell proliferation capacity, and reduced Akt and GSK-3β phosphorylation. Similarly, Akt inhibition reversed the upregulation of U2SURP and IGF2BP3 by high glucose, while Akt activation attenuated the suppressive effect of metformin on these genes. Conclusion  Under high glucose conditions, IGF2BP3 promotes colon cancer cell proliferation by regulating U2SURP in an m6A-dependent manner. Metformin mitigates this pro-proliferative effect by inhibiting the Akt signaling pathway, thereby reducing the expression of U2SURP and IGF2BP3.