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

¹ Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
² Department of Animal Sciences, University of Illinois at Urbana, Champaign, Urbana, Illinois

Address correspondence and reprint requests to Dr. Robert S. Sherwin, Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology, 300 Cedar St., TAC S141, New Haven, CT. E-mail: robert.sherwin{at}yale.edu

Abbreviations: BIC, bicuculline methiodide; K_ATP channel, ATP-sensitive K⁺ channel; VMH, ventromedial hypothalamus

OBJECTIVE—To determine whether alterations in counterregulatory responses to hypoglycemia through the modulation of ATP-sensitive K⁺ channels (K_ATP channels) in the ventromedial hypothalamus (VMH) are mediated by changes in GABAergic inhibitory tone in the VMH, we examined whether opening and closing K_ATP channels in the VMH alter local GABA levels and whether 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 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, 3) the K_ATP channel closer glybenclamide, 4) diazoxide plus the GABA_A receptor agonist muscimol, or 5) glybenclamide plus the GABA_A receptor antagonist bicuculline methiodide (BIC) before performance of a hypoglycemic clamp. Throughout, VMH GABA levels were measured using microdialysis.

RESULTS—As expected, diazoxide suppressed glucose infusion rates and increased glucagon and epinephrine responses, whereas glybenclamide 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 that VMH GABA levels decreased 22% with the onset of hypoglycemia in controls. Diazoxide caused a twofold greater decrease in GABA levels, and glybenclamide increased VMH GABA levels by 57%.

CONCLUSIONS—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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