Although several factors may interact with the efficacy of metformin on endogenous glucose production, further work on the metformin mechanism should focus on cell and animal models with compromised intracellular metabolite homeostasis that more closely simulate the dysregulation in poorly controlled type 2 diabetes, to determine whether AMPK-independent repression of G6pc by metformin predominates in the compromised metabolic state. This evidence concerns the gene PRKAB1 and type 2 diabetes mellitus.