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Aims. Within the brain, subgroups of neurons respond differently to altered glucose concentrations. Identification of neuropeptide Y in hypothalamic neurons that sense glucose suggests a role for neuropeptide Y in glucose sensing. Using in vitro and in vivo techniques to monitor transmitter release, we investigated whether lowering glucose concentration affects the release of neuropeptide Y from the brain, and whether this process is altered in Type I (insulin-dependent) diabetes mellitus. Methods. Male Sprague-Dawley rats were treated with 48 mg/kg streptozotocin or vehicle intravenously. The effect of reduced glucose on endogenous neuropeptide Y overflow from slices of hypothalamus and medulla incubated in Krebs solution was examined 4 weeks later. The hypothalamus was separated into a dorsal region containing the paraventricular nucleus and a ventral region containing the arcuate nucleus. Results. Streptozotocin-induced diabetes increased basal neuropeptide Y overflow in the dorsal and ventral hypothalamus (p<0.05) but not the medulla. In vitro neuropeptide Y overflow was reduced by low glucose in the dorsal hypothalamus in diabetic, but not in control rats. No effect of reduced glucose was observed in the ventral hypothalamus or medulla. In vivo push-pull studies in the paraventricular nucleus also showed greater neuropeptide Y overflow in diabetic rats relative to control rats (p<0.05). Insulininduced hypoglycaemia induced a decrease in neuropeptide Y overflow in diabetic rats, while an increase was observed in control rats (p<0.05). Conclusion. These region-specific effects of low glucose on neuropeptide Y overflow in diabetic rats support a part for neuropeptide Y in altered glucose sensing in Type I diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1332[Diabetologia ( -1339