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Diabetes 53:2542-2551, 2004
© 2004 by the American Diabetes Association, Inc.

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

From the Diabetes Endocrine Research Center, Yale School of Medicine, New Haven, Connecticut

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 hypoglycemia. The molecular mechanisms used by glucose-sensing neurons are uncertain but may involve cell surface ATP-sensitive K+ channels (KATP channels) analogous to those of the pancreatic ß-cell. We examined whether the delivery of sulfonylureas directly into the brain to close KATP channels would modulate counterregulatory hormone responses to either brain glucopenia (using intracerebroventricular 5-thioglucose) or systemic hypoglycemia in awake chronically catheterized rats. The closure of brain KATP channels by global intracerebroventricular perfusion of sulfonylurea (120 ng/min glibenclamide or 2.7 µg/min tolbutamide) 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 glibenclamide (0.1% of the intracerebroventricular dose) also suppressed hormonal responses to systemic hypoglycemia. We conclude that hypothalamic KATP channel activity plays an important role in modulating the hormonal counterregulatory responses triggered by decreases in blood glucose. Our data suggest that closing of KATP channels in the VMH (much like the ß-cell) impairs defense mechanisms against glucose deprivation and therefore could contribute to defects in glucose counterregulation.

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{at}yale.edu


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Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2004 by the American Diabetes Association.