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Metformin exerts its plasma glucose-lowering therapeutic effect primarily through inhibition of hepatic gluconeogenesis. However, the precise molecular mechanism by which metformin inhibits hepatic gluconeogenesis is still unclear. Although inhibition of mitochondrial complex I is frequently invoked as metformin’s primary mechanism of action, the metabolic effects of complex I inhibition have not been thoroughly evaluated in vivo. Here, we show that acute portal infusion of piericidin A, a potent and specific complex I inhibitor, does not reduce hepatic gluconeogenesis in vivo. In contrast, we show that metformin, phenformin, and galegine selectively inhibit hepatic gluconeogenesis from glycerol. Specifically, we show that guanides/biguanides interact with complex IV to reduce its enzymatic activity, leading to indirect inhibition of glycerol-3-phosphate (G3P) dehydrogenase (GPD2), increased cytosolic redox, and reduced glycerol-derived gluconeo-genesis. We report that inhibition of complex IV with potassium cyanide replicates the effects of the guanides/biguanides in vitro by selectively reducing glycerol-derived gluconeogenesis via increased cytosolic redox. Finally, we show that complex IV inhibition is sufficient to inhibit G3P-mediated respiration and gluconeo-genesis from glycerol. Taken together, we propose a mechanism of metformin action in which complex IV–mediated inhibition of GPD2 reduces glycerol-derived hepatic gluconeogenesis. [ABSTRACT FROM AUTHOR]