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Amplified hormonal counterregulatory responses to hypoglycemia in rats following systemic delivery of a SUR-1-selective potassium channel opener?

Yale University School of Medicine, Department of Internal Medicine and Endocrinology, New Haven, CT¹; and
Pharmacology Research 3, Novo Nordisk, Malov, Denmark²

Objective: In glucose-sensing neurons K_ATP channels are thought to translate metabolic signals into an alteration in neuronal firing rates. Since 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, NN414, to amplify counterregulatory response to hypoglycemia.

Research Design and Methods: In vivo dose response studies with NN414 delivered intravenously to normal Sprague-dawley rats prior to the induction of controlled hypoglycemia were performed. Based on these studies the potential for NN414 to restore counterregulatory responses in chronically-cannulated non-diabetic and diabetic BB rats was explored using the in vivo hyperinsulinemic hypoglycemic clamp technique.

Results: NN414 delivered systemically amplified epinephrine responses during acute hypoglycemia, and showed a persisting effect to amplify the epinephrine response when given 24 hours prior to the hypoglycemic study. Local delivery of a potassium channel blocker to the ventromedial hypothalamus (VMH) reversed the effects of systemic NN414. In addition, NN414 amplified the epinephrine response to hypoglycemia in both non-diabetic and diabetic BB rats with defective hormonal counterregulation.

Conclusions: These studies demonstrate in a variety of rodent models that systemic delivery of Kir6.2/SUR1-selective potassium channel openers 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 (HAAF) in type 1 diabetes.

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