INS and neoplasm: Metformin exhibits anticancer actions via both direct and indirect effects [32]: the indirect effects include reduction of circulating glucose and insulin levels, and suppression of tumor progression by indirectly modulating IGF-1 signaling, which promotes tumor cell growth [33], while the direct effects include initiation of cell-cycle arrest, suppression of epithelial-mesenchymal transition (EMT), and inhibition of tumorigenesis and cancer progression [33].