The brain has evolved specialized glucosensing neurons which participate in glucose and overall energy homeostasis in the body. Glucosensing neurons utilize glucose as a signaling molecule to alter their firing rate, as opposed to the vast majority of neurons which primarily utilize glucose to fuel their metabolic needs [1]. Oomura [2] and Anand [3] and their co-workers first demonstrated such neurons in both the fore-and hindbrain in 1964. Although these neurons can respond directly or indirectly to either the complete absence of glucose or to levels as high as 20 mM [4][5][6][7][8][9][10][11], it is likely that their primary range is between 0.5-3.5 mM under physiologic conditions [12,13]. Mounting evidence supports a role for glucokinase (GK) as the gatekeeper for neuronal glucosensing within this physiologic range [11,14]. Importantly, glucosensing neurons reside in brain areas known to play critical regulatory roles in energy homeostasis and neuroendocrine and autonomic function [15][16][17][18].Glucose sensing neurons are either excited (glucose excited; GE) or inhibited (glucose inhibited; GI) by rising ambient glucose levels [6,7,9,10]. However, early studies used extracellular recording techniques to monitor neuronal activity at glucose levels virtually never seen by the living brain, i.e. 0 vs. 10-20 mM [6,10]. Neurophysiologic studies have provided direct evidence that GE neurons function much like the pancreatic -cell where elevated glucose levels increase the ATP/ADP ratio and inactivate (close) an inwardly rectifying K ϩ pore-forming unit (Kir6.2) of the ATP-sensitive K ϩ (K ATP ) channel [4,5,9,10,19]. This channel on GE neurons is similar, but not completely identical to