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460 nature neuroscience• volume 4 no 5• may 2001 news and views weight in Kir6. 2–/–mice are required to shed light on this important issue. It is curious that mammals have evolved mechanisms for dealing with severe hypoglycemia, a condition that almost never occurs in nature. Evolutionary origins aside, the counter-regulatory response has gained considerable clinical significance since the advent of insulin therapy for diabetes mellitus. Episodes of inadvertent insulin-induced hypoglycemia have become commonplace as clinicians attempt to maintain ever-tightening control of blood glucose levels. Further, repeated bouts of hypoglycemia lead to reduced awareness of hypoglycemia and attenuation of the counter-regulatory response10, 11. This neurohumoral response is designed to mobilize every last ounce of the body’s glucose stores to prevent brain damage. Sympatho-adrenal activation releases norepinephrine and epinephrine from sympathetic nerves and the adrenal medulla. Corticosterone (in rodents) is released from the adrenal cortex, growth hormone from the pituitary and glucagon from the α-cells of the pancreas. In Kir6. 2–/–mice, the brain-mediated glucagon component of the counter-regulatory response to hypoglycemia is attenuated, and the ability to correct hypoglycemia is impaired. It is unclear how the remainder of the counter-regulatory response is affected by deletion of Kir6. 2. No corticosterone or growth hormone levels were measured, and the epinephrine response seemed to be intact. Because the pathways mediating these other responses and those regulating glucagon release are very different, this is an important issue. Methodological problems make it difficult to interpret the epinephrine response to hypoglycemia. Both Kir6. 2+/+ and Kir6. 2–/–mice had enormous elevations of basal epinephrine levels (almost 50 times those found in undisturbed animals), which might have obscured any deficit of hypoglycemia-induced epinephrine release in the Kir6. 2–/–mice. Thus, additional studies in Kir6. 2–/–mice are required to gain a full understanding of the role of the KATP channel in this complex neurohumoral reaction. The most important and unambiguous finding of this study is that VMH GR neurons require the Kir6. 2 subunit of the KATP channel to sense glucose. As the authors point out, this channel is there are other glucosensing mechanisms in the body that are likely to be involved in the counter-regulatory response, but may be independent of the KATP channel. These include glucose-sensitive neurons, which increase their firing rate as glucose levels fall, and glucosensing elements in the portal vein15. That both glucoprivic feeding and the counter-regulatory response are not totally abolished in Kir6. 2–/–mice suggests that these other glucosensing mechanisms do not require the KATP channel. In summary, the current studies in the Kir6. 2–/–mouse demonstrate that an intact KATP channel is critical to the functioning of GR neurons in the VMH. In addition, a functional KATP channel seems to be required to mount a normal counter-regulatory response and to increase food intake when intracellular glucose metabolism falls to pathologically low levels. However, further studies will be required before we can accept the contention that VMH GR neurons are the specific effectors of these responses or that they are truly involved in the regulation of blood glucose levels and food intake under physiological conditions.