Metformin mitigated tumor growth in HFD-fed obese mice, and the tumor growth inhibition was associated with reductions in body mass, hyperglycemia, hyperinsulinemia, insulin resistance, WBCs, lymphocytes, neutrophils, plasma levels of leptin, soluble P-selectin, TGF-β1 and HMGB1, as well as the tumor levels of cyclin D1, β-catenin, HMGB1, RAGE, Akt phosphorylation, Smad2/3 phosphorylation, GLUT1, PKM2, SLC1A5, SLC7A5, glutaminase, CD62P and MPO, while there was an increase in plasma levels of glutamine. This evidence concerns the gene SMAD2 and Insulin resistance.