INS and neoplasm: In addition, metformin indirectly exerts an anti-tumor effect via reducing serum insulin level, repressing the signaling pathway of insulin and insulin-like growth factor 1 (I/IGF-1)/phosphoinositide 3-kinase (PI3K)/Akt/mTOR [25–27] or I/IGF-1/Ras/Raf/MEK/ERK [29, 30] (Fig 3).