These results demonstrate that FGF21 functions physiologically and pharmacologically to prevent type 2 diabetic lipotoxicity-induced cardiomyopathy through activation of both AMPK–AKT2–NRF2-mediated antioxidative pathway and AMPK–ACC–CPT-1-mediated lipid-lowering effect in the heart. This evidence concerns the gene NFE2L2 and type 2 diabetes mellitus.