Acute 2DG-induced glucoprivation or dexamethasone abolishes 2DG-induced glucoregulatory responses to subsequent...

Behavioral, neuroendocrine, and autonomic responses to glucoprivation are impaired after a glucoprivic episode. A life-threatening manifestation of this effect, known as hypoglycemia-associated autonomic failure (HAAF), occurs in diabetic patients as a result of prior inadvertent hypoglycemia resulting from insulin therapy. Glucocorticoids, which are elevated by glucoprivation, have been implicated in the pathogenesis of HAAF. The goal of the present study was to examine the effect of glucocorticoids on glucoregulatory responses in a rat model of HAAF. 2-deoxy-D-glucose (2DG; 200 mg/kg) was used to induce glucoprivation. Rats were injected with saline, 2DG, or the synthetic glucocorticoid, dexamethasone (DEX; 250 microg/rat) in the morning. Then 6 h later, rats were injected with 2DG, and their feeding and hyperglycemic responses were measured. Both 2DG and DEX in the morning eliminated glucoprivic feeding and hyperglycemic responses in the afternoon test. Epinephrine (0.3 mg/kg) administration in the afternoon elicited marked hyperglycemia in animals given 2DG that morning, demonstrating that glycogen depletion from morning glucoprivation was not responsible for the absence of the hyperglycemic response in the afternoon test. The effects of prior saline or 2DG treatment on subsequent glucoprivic feeding were also examined in adrenalectomized rats in which the source of endogenous glucocorticoids was removed. In these animals, prior glucoprivation did not attenuate 2DG-induced feeding in the afternoon test. These findings demonstrate that a single glucoprivic episode is sufficient to cause impairment in glucoregulatory responses to a second glucoprivic episode in the same day. In addition, these results strongly implicate glucocorticoids in the pathogenesis of HAAF.