Scientists have proposed many mechanisms of action to explain the glucose-lowering benefits of metformin, the first-line treatment for type 2 diabetes. But previous studies typically used doses much greater than those given therapeutically. Now, studying rats receiving clinically relevant doses of metformin, researchers report the compound blocks conversion of select substrates into glucose in a redox-dependent manner. This would not be consistent with other proposed mechanisms by which metformin inhibits gluconeogenesis, a process that turns noncarbohydrate carbon substrates into glucose in the liver and is abnormal in type 2 diabetes, the researchers say (Nat. Med. 2018, DOI: 10.1038/s41591-018-0125-4). Gerald Shulman of Yale University School of Medicine and colleagues tracked 13C-labeled substrates in both diabetic and nondiabetic rodents. They found metformin inhibited liver gluconeogenesis starting from a subset of substrates whose conversion to glucose relies on the redox state of liver cells’ cytosol. They also showed that metformin treatment made the cytosol more reduced. When the team prevented this more-reduced state of the cytosol, metformin no longer could block liver gluconeogenesis. Shulman says these results suggest that new therapies targeting the liver’s cytosolic redox state might be an effective way to treat type 2 diabetes.