INS and cancer: Currently, there are two central models to explain the antiproliferative effects of metformin on cancer cells: 1) that metformin acts indirectly on tumor cell growth by lowering systemic insulin and insulin-like growth factor-1 (IGF-1) levels through inhibition of hepatic gluconeogenesis, thus suppressing the growth of insulin/IGF-1-dependent tumor cells; or 2) that metformin acts directly on complex I of tumor cells to reduce OXPHOS and other metabolic activities of tumor cells [10,11].