Amplified hormonal counterregulatory responses to hypoglycemia in rats after systemic delivery of a SUR-1-selective K(+) channel opener?

Abstract

In glucose-sensing neurons, ATP-sensitive K(+) channels (K(ATP) channels) are thought to translate metabolic signals into an alteration in neuronal firing rates. Because these neurons express the Kir6.2/SUR-1 isoform of the K(ATP) channel, we sought to examine the therapeutic potential of the SUR-1-selective potassium channel opener (KCO), NN414, to amplify counterregulatory response to hypoglycemia. In vivo dose-response studies with NN414 delivered intravenously to normal Sprague-Dawley rats before the induction of controlled hypoglycemia were performed. Based on these studies, the potential for NN414 to restore counterregulatory responses in chronically cannulated nondiabetic and diabetic BB rats was explored using the in vivo hyperinsulinemic-hypoglycemic clamp technique. NN414 delivered systemically amplified epinephrine responses during acute hypoglycemia and showed a persisting effect to amplify the epinephrine response when given 24 h before the hypoglycemic study. Local delivery of a potassium-channel blocker to the ventromedial hypothalamus reversed the effects of systemic NN414. In addition, NN414 amplified the epinephrine response to hypoglycemia in both nondiabetic and diabetic BB rats with defective hormonal counterregulation. These studies demonstrate in a variety of rodent models that systemic delivery of Kir6.2/SUR-1-selective KCOs enhance the glucose counterregulatory response to insulin-induced hypoglycemia. Future studies in human subjects are now required to determine their potential as a therapy for hypoglycemia-associated autonomic failure in type 1 diabetes.