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Increased GABAergic Tone in the Ventromedial Hypothalamus Contributes to Suppression of Counterregulatory Reponses After Antecedent Hypoglycemia

¹ Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
² Department of Genetics, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut

Corresponding author: Dr. Robert S. Sherwin, Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology, 300 Cedar St., TAC S141, New Haven, CT 06520. E-mail: robert.sherwin{at}yale.edu

Abbreviations: ECF, extracellular fluid; GABA, -aminobutyric acid; GAD, glutamic acid decarboxylase; HAAF, hypoglycemia-associated autonomic failure; VMH, ventromedial hypothalamus

OBJECTIVE—We have previously demonstrated that modulation of -aminobutyric acid (GABA) inhibitory tone in the ventromedial hypothalamus (VMH), an important glucose-sensing region in the brain, modulates the magnitude of glucagon and sympathoadrenal responses to hypoglycemia. In the current study, we examined whether increased VMH GABAergic tone may contribute to suppression of counterregulatory responses after recurrent hypoglycemia.

RESEARCH DESIGN AND METHODS—To test this hypothesis, we quantified expression of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), in the VMH of control and recurrently hypoglycemic rats. Subsequently, we used microdialysis and microinjection techniques to assess changes in VMH GABA levels and the effects of GABA_A receptor blockade on counterregulatory responses to a standardized hypoglycemic stimulus.

RESULTS—Quantitative RT-PCR and immunoblots in recurrently hypoglycemic animals revealed that GAD₆₅ mRNA and protein were increased 33 and 580%, respectively. Basal VMH GABA concentrations were more than threefold higher in recurrently hypoglycemic animals. Furthermore, whereas VMH GABA levels decreased in both control and recurrently hypoglycemic animals with the onset of hypoglycemia, the fall was not significant in recurrently hypoglycemic rats. During hypoglycemia, recurrently hypoglycemic rats exhibited a 49–63% reduction in glucagon and epinephrine release. These changes were reversed by delivery of a GABA_A receptor antagonist to the VMH.

CONCLUSIONS—Our data suggest that recurrent hypoglycemia increases GABAergic inhibitory tone in the VMH and that this, in turn, suppresses glucagon and sympathoadrenal responses to subsequent bouts of acute hypoglycemia. Thus, hypoglycemia-associated autonomic failure may be due in part to a relative excess of the inhibitory neurotransmitter, GABA, within the VMH.

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