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Metformin is a widely prescribed drug for treatment of type 2 diabetes, although no cellular mechanism of action has been established. To determine whether in vivo metformin treatment alters mitochondrial function in skeletal muscle, respiratory O₂ flux and H₂O₂ emission were measured in saponin-permeabilized myofibers from lean and obese (fa/fa) Zucker rats treated for 4weeks with metformin. Succinate- and palmitoylcarnitine-supported respiration generated greater than twofold higher rates of H₂O₂ emission in myofibers from untreated obese versus lean rats, indicative of an obesity-associated increased mitochondrial oxidant emitting potential. In conjunction with improved glycemic control, metformin treatment reduced H₂O₂ emission in muscle from obese rats to rates near or below those observed in lean rats during both succinate- and palmitoylcarnitine-supported respiration. Surprisingly, metformin …