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

Abstract

Objective: We have previously demonstrated that modulation of 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 following recurrent hypoglycemia (RH).

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 RH 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: QRT-PCR and immunoblots in RH animals revealed that GAD₆₅ mRNA and protein were increased 33 and 580%, respectively. Basal VMH GABA concentrations were more than 3-fold higher in RH animals. Furthermore, while VMH GABA levels decreased in both control and RH animals with the onset of hypoglycemia, the fall was not significant in RH rats. During hypoglycemia, RH 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.

Conclusion: Our data suggest that RH increases GABAergic inhibitory tone in the VMH and 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.