Centrally administered metformin inhibited brain Rap1 and reduced high blood sugar. The relevant cells were SF1 neurons, which showed a measurable increase in activity upon metformin administration to the brain. Deleting brain Rap1 blocked the effect; forcing Rap1 activation abolished it. Does metformin get into the brain? Mice lacking brain Rap1 stopped responding to systemically administered low-dose metformin but remained responsive to other antidiabetic agents.