In summary, the present study indicates that treatment with the anti-diabetic agent metformin, which has a preventive effect on HCC development based on case-control studies and meta-analyses of human trials [23–25], suppresses DEN-induced liver tumorigenesis in db/db mice probably by improving insulin resistance, inhibiting excess activation of the Akt/mTOR signaling, and ameliorating adipokine imbalance. Here, INS is linked to hepatocellular carcinoma.