Are Metformin Doses Used in Murine Cancer Models Clinically Relevant?

An important mechanism of action of metformin as an antidiabetic drug involves inhibition of hepatic gluconeogenesis, but the molecular basis for this is controversial. A recent perspective (He and Wondisford, 2015) argued that direct action of the drug on AMPK is of key importance and occurs at clinically relevant concentrations of ∼70 μM. However, that review cited conflicting studies, which concluded either that AMPK-independent mechanisms are important in metformin action, or that AMPK activation plays a role but is secondary to energetic stress resulting from inhibition of oxidative phosphorylation by the drug.