GCK and diabetes mellitus: In this review, we will: (i) first provide an outline of the evidence that brain glucose sensing is important for glucose homeostasis, (ii) give an overview of brain glucose-sensing mechanisms including those using glucokinase, (iii) then describe the current data supporting a role for brain glucokinase in the central control of glucose homeostasis and (iv) discuss how these processes may become altered in diabetes and related metabolic disorders.