Metformin’s core mechanism revealed: gut mitochondria drive its glucose-lowering effect

A Nature Metabolism study shows metformin lowers blood sugar primarily by inhibiting mitochondrial complex I in intestinal cells, causing those cells to burn more glucose via glycolysis. Liver-level action is less likely since liver concentrations of metformin are low. In mice engineered with a backup intestinal enzyme, the drug’s glucose-lowering effect dropped about 80%, suggesting intestinal complex I inhibition as the main acute mechanism, though researchers caution about translating findings to humans and acknowledge additional targets may exist.