Metformin targets mitochondrial complex I to lower blood glucose levels

Metformin is among the most prescribed anti-diabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae protein NDI1 to determine whether the glucose lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose. Overall design: The objective of this study was to use NDI1 in vivo to determine whether metformin mediates its blood glucose lowering effect through inhibition of mitochondrial complex I. RNA-seq was performed on bulk liver samples from wild-type and NDI1+ mice to confirm NDI1 expression in the liver.