Hypothalamic ATP-sensitive K + Channels Play a Key Role in Sensing Hypoglycemia and Triggering Counterregulatory Epinephrine and Glucagon Responses

Abstract

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 (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 counterregulatory hormone responses to either brain glucopenia (using intracerebroventricular 5-thioglucose) or systemic hypoglycemia in awake chronically catheterized rats. The closure of brain K ATP channels by global intracerebroventricular perfusion of sulfonylurea (120 ng/min glibenclamide or 2.7 g/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 K ATP channel activity plays an important role in modulating the hormonal counterregulatory responses triggered by decreases in blood glucose. Our data suggest that closing of K ATP channels in the VMH (much like the ␤-cell) impairs defense mechanisms against glucose deprivation and therefore could contribute to defects in glucose counterregulation.

Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene

“…The response to hypoglycaemia may be moderated by the Kir6.2 mutation. K ATP channels are present in the glucose-sensing neurons of the ventromedial hypothalamus that play a key role in the central detection of hypoglycaemia and the initiation of protective counter-regulatory epinephrine (adrenaline) and glucagon responses [14][15][16]. There was undetected hypoglycaemia when on insulin in our patient but formal studies of the hypoglycaemia response in these patients are required.…”

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

“…rich with leptin receptors and glucose-responsive elements analogous to those of pancreatic beta cells (Yang et al, 1999;Miki et al, 2001;Evans et al, 2004;McCrimmon et al, 2004;Squires et al, 2005). Accordingly, the VMN mediates counter-regulatory responses to hypoglycemia and energy balance responses to leptin (Jacob et al, 1997;Satoh et al, 1997;Choi et al, 1999;Dube et al, 1999;Elias et al, 2000;Borg et al, 2003).…”

Glucose sensing and the pathogenesis of obesity and type 2 diabetes

“…For instance, intracerebroventricular or direct VMH injection of the K ATP channel inhibitor glibenclamide blocked the counter-regulatory response to a hypoglycemic clamp. 67 Inactivation of K ATP channel by Kir6.2 gene knockout also leads to impaired glucagon response, and this was correlated with suppressed glucose-regulated firing activity of VMH neurons. 68 In contrast, the activation of ATPsensitive K þ channels in the VMH amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats.…”