Regulation of organelle function by metformin

Metformin ameliorates hyperglycemia without the side effects of lactic acidosis or hypoglycemia. Metformin lowers the blood glucose level by decreasing hepatic glucose production in the liver and by increasing glucose uptake in the muscle. Recent studies show that metformin induces cell death in certain cancer cell lines by interfering with the metabolism of the cancer cells. Therefore, understanding the mechanisms of action for metformin will provide insights into how to better treat diabetes and other metabolic disorders and also into the development of new therapeutic drugs. One of the best understood molecular targets of metformin is the mitochondrial complex I. However, given metformin's broad effects on metabolism, it could act on multiple targets. In this review, we summarize current findings in metformin's mechanisms of action regarding its known targets in mitochondria and known effects in cancer cell lines. Then, we introduce endosomal Na⁺ /H⁺ exchangers and the V-ATPase as new potential targets of metformin's action. Finally, we will discuss the hypothesis that metformin directly acts on endosome/lysosome regulation so as to regulate metabolism and ultimately alleviate type 2 diabetes. © 2017 IUBMB Life, 69(7):459-469, 2017.