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ATP-Sensitive Potassium Channels Regulate the Release of GABA in the Ventromedial Hypothalamus During Hypoglycemia

¹Yale University School of Medicine, Department of Internal Medicine - Section of Endocrinology, New Haven, CT, 06520 U.S.A
²University of Illinois at Urbana-Champaign, Department of Animal Sciences, Urbana, IL, 61801 U.S.A

Correspondence: robert.sherwin{at}yale.edu

Key Words: GABA • hypoglycemia • microdialysis • microinjection • ventromedial hypothalamus • diazoxide • glybenclamide • K_ATP channel

OBJECTIVE:: To determine whether alterations in counterregulatory responses to hypoglycemia through the modulation of ATP-sensitive potassium (K_ATP) channels in the ventromedial hypothalamus (VMH) is mediated by changes in GABAergic inhibitory tone in the VMH, we examined whether opening and closing K_ATP channels in the VMH alters local GABA levels and if the effects of modulating K_ATP channel activity within the VMH can be reversed by local modulation of GABA receptors. Research Design and Methods: Rats were cannulated and bilateral guide cannulas were inserted to the level of the VMH. Eight days later, the rats received a VMH microinjection of either 1) vehicle, 2) the K_ATP channel opener, diazoxide (DZ), 3) the K_ATP channel closer, glybenclamide (GLYB), 4) DZ + the GABA_A receptor agonist, muscimol (MUS) or 5) GLYB + the GABA_A receptor antagonist, bicuculline methiodide (BIC) prior to performance of a hypoglycemic clamp. Throughout, VMH GABA levels were measured using microdialysis. Results: As expected, DZ suppressed glucose infusion rates and increased glucagon and epinephrine responses, whereas GLYB raised glucose infusion rates in conjunction with reduced glucagon and epinephrine responses. These effects of K_ATP modulators were reversed by GABA_A receptor agonism and antagonism, respectively. Microdialysis revealed VMH GABA levels decreased 22% with the onset of hypoglycemia in controls. DZ caused a 2-fold greater decrease in GABA levels and GLYB increased VMH GABA levels by 57%. Conclusion: Our data suggests that K_ATP channels within the VMH may modulate the magnitude of counterregulatory responses by altering release of GABA within that region.

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