Hypoglycaemia or glucopenia trigger protective responses including the stimulation of feeding. These responses may become impaired in some type 1 diabetic patients following aggressive insulin therapy. We hypothesized that glucoprivation might be sensed by hypothalamic glucose-sensing neurones using the specialised glucose-sensing molecule glucokinase (GK) and have recently shown that ICV delivery of GK inhibitors such as glucosamine (GSN) boosts feeding in Sprague Dawley (SD) rats (Evans et al., 2005). Here, we examined whether low dose GSN (15 nmol/min- below the orexigenic dose) can boost defensive feeding when delivered in combination with 2-deoxyglucose (2DG) induced glucopenia. We created a model of hypoglycaemia unawareness in male SD rats by exposure to 3 days of insulin injections [INS] or saline [SAL] in controls. We measured feeding responses on day 4 to brain glucopenia (ICV 2DG) with/ without GSN. We studied three groups of animals: (1) SAL injected rats with day 4 ICV vehicle and 2DG (SAL-ECF-2DG) (2) INS injected rats with day 4 ICV vehicle and 2DG (INS-ECF-2DG) or (3) INS injected rats with day 4 ICV GSN and 2DG (INS-GSN-2DG). Antecedent INS injections suppressed glucoprivic feeding response (INS-ECF-2DG vs SAL-ECF-2DG- see figure). ICV GSN restored feeding response to a level similar to that seen in control rats (see figure). We then reasoned that glucoprivic feeding would be impaired in mice deficient in GK. GENA348 mice with defective GK (Toye et al., 2004) displayed markedly blunted incremental feeding response to glucopenia following intraperitoneal 2DG injections relative to wild type BALB-C mice (table). Together, our data suggest a role for hypothalamic GK in the control of protective feeding responses to glucopenia. These findings also imply that hypothalamic GK may perhaps represent a novel target for restoring protective hunger symptoms to hypoglycaemia in type 1 diabetes.