Activation of ATP-sensitive K⁺ channels in the ventromedial hypothalamus amplifies counterregulatory hormone responses to hypoglycemia in normal and recurrently hypoglycemic rats

The mechanism(s) by which glucosensing neurons detect fluctuations in glucose remains largely unknown. In the pancreatic β-cell, ATP-sensitive K⁺ channels (K_ATP channels) play a key role in glucosensing by providing a link between neuronal metabolism and membrane potential. The present study was designed to determine in vivo whether the pharmacological opening of ventromedial hypothalamic K_ATP channels during systemic hypoglycemia would amplify hormonal counterregulatory responses in normal rats and those with defective counterregulation arising from prior recurrent hypoglycemia. Controlled hypoglycemia (approximately ∼2.8 mmol/l) was induced in vivo using a hyperinsulinemic (20 mU x kg^-1 x min^-1) glucose clamp technique in unrestrained, overnight-fasted, chronically catheterized Sprague-Dawley rats. Immediately before the induction of hypoglycemia, the rats received bilateral ventromedial hypothalamic microinjections of either the potassium channel openers (KCOs) diazoxide and NN414 or their respective controls. In normal rats, both KCOs amplified epinephrine and glucagon counterregulatory responses to hypoglycemia. Moreover, diazoxide also amplified the counterregulatory responses in a rat model of defective hormonal counterregulation. Taken together, our data suggest that the K_ATP channel plays a key role in vivo within glucosensing neurons in the ventromedial hypothalamus in the detection of incipient hypoglycemia and the initiation of protective counterregulatory responses. We also conclude that KCOs may offer a future potential therapeutic option for individuals with insulin-treated diabetes who develop defective counterregulation.