Hypothalamic ATP-sensitive K  Channels Play a Key Role in Sensing Hypoglycemia and Triggering Counterregulatory Epinephrine and Glucagon Responses Mark L. Evans, Rory J. McCrimmon, Daniel E. Flanagan, Tara Keshavarz, Xiaoning Fan, Ewan C. McNay, Ralph J. Jacob, and Robert S. Sherwin It has been postulated that specialized glucose-sensing neurons in the ventromedial hypothalamus (VMH) are able to detect falling blood glucose and trigger the release of counterregulatory hormones during hypogly- cemia. The molecular mechanisms used by glucose-sens- ing neurons are uncertain but may involve cell surface ATP-sensitive K  channels (K ATP channels) analogous to those of the pancreatic -cell. We examined whether the delivery of sulfonylureas directly into the brain to close K ATP channels would modulate counter- regulatory hormone responses to either brain gluco- penia (using intracerebroventricular 5-thioglucose) or systemic hypoglycemia in awake chronically cathe- terized rats. The closure of brain K ATP channels by global intracerebroventricular perfusion of sulfonyl- urea (120 ng/min glibenclamide or 2.7 g/min tolbut- amide) suppressed counterregulatory (epinephrine and glucagon) responses to brain glucopenia and/or systemic hypoglycemia (2.8 mmol/l glucose clamp). Local VMH microinjection of a small dose of gliben- clamide (0.1% of the intracerebroventricular dose) also suppressed hormonal responses to systemic hypo- glycemia. We conclude that hypothalamic K ATP channel activity plays an important role in modulating the hor- monal counterregulatory responses triggered by de- creases in blood glucose. Our data suggest that closing of K ATP channels in the VMH (much like the -cell) impairs defense mechanisms against glucose depriva- tion and therefore could contribute to defects in glu- cose counterregulation. Diabetes 53:2542–2551, 2004 T he benefits of lowering average blood glucose levels in diabetes to reduce the risk of long-term complications are well established. In clinical practice, the degree to which this can be achieved is often limited by the increased risk of hypogly- cemia that accompanies intensified glucose-lowering reg- imens (1,2). When healthy, blood glucose levels are normally maintained within relatively narrow limits. A fall in blood glucose is rapidly detected and a series of compensatory homeostatic responses are triggered that tend to prevent or limit hypoglycemia and to restore euglycemia. These responses include secretion of the counterregulatory hormones glucagon and epinephrine, which promote endogenous glucose production and limit tissue utilization of glucose and the generation of typical warning symptoms. These protective responses against hypoglycemia are disrupted in diabetes. Within 5 years of diagnosis, almost all patients with type 1 diabetes will develop defective secretion of the counterregulatory hor- mone glucagon during hypoglycemia (3). This leaves epi- nephrine as the major hormonal counterregulatory defense against low blood glucose. However, a significant number of patients will also develop additional deficien- cies in epinephrine and other neurohumoral responses to hypoglycemia associated with the loss of symptomatic awareness of hypoglycemia (3). The combination of im- paired counterregulation and hypoglycemia unawareness significantly increases the risk of suffering severe episodes of hypoglycemia (4,5). To trigger protective counterregulatory neurohumoral responses, hypoglycemia must first be detected. Although low blood glucose may be detected, at least in part, by peripheral sensors (6 –9), much evidence suggests that hypoglycemia is sensed predominantly by the brain (10 – 13) by glucose-sensing neurons in the ventromedial hypo- thalamus (VMH), with ventromedial and arcuate nuclei probably playing a key role (14 –16). Glucose-sensing neurons may be either stimulated (glucose excited) or inhibited (glucose inhibited) by a rise in glucose (17). The mechanisms used by specialized glucose excited and inhibited neurons to sense changes in glucose remain undetermined, but recent in vitro evidence suggests that there may be parallels with pancreatic -cell glucose From the Diabetes Endocrine Research Center, Yale School of Medicine, New Haven, Connecticut. Address correspondence and reprint requests to Professor Robert Sherwin, Diabetes Endocrine Research Center, Fitkin 1, Yale School of Medicine, 333 Cedar St., New Haven, CT 06520. E-mail: robert.sherwin@yale.edu. M.L.E. and R.J.M. contributed equally to this study. M.L.E. is currently affiliated with the Department of Medicine, Adden- brookes Hospital, University of Cambridge, Cambridge, U.K. Received for publication 29 March 2004 and accepted in revised form 13 July 2004. 5TG, 5-thioglucose; aECF, artificial extracellular fluid; K ATP channel, ATP- sensitive K + channel; KIR, pore-forming subunit; SUR, sulfonylurea receptor subunit; VMH, ventromedial hypothalamus. © 2004 by the American Diabetes Association. 2542 DIABETES, VOL. 53, OCTOBER 2004