Hypoglycemia elicits an integrated array of CNS-mediated counterregulatory responses, including activation of the hypothalamic-pituitary-adrenal axis. The role of antecedent adrenocortical hypersecretion in impaired
glucose counterregulation remains controversial. The present studies utilized the selective, nonsteroidal
glucocorticoid receptor antagonist,
CP-472555, as a pharmacological tool to investigate the hypothesis that
hypoglycemic hypercorticosteronemia modulates CNS efferent autonomic and neuroendocrine motor responses to recurring
insulin-induced
hypoglycemia via
glucocorticoid receptor-dependent mechanisms. Groups of adult male rats were injected s.c. with either one or four doses of the intermediate-acting
insulin,
Humulin neutral
protamine Hagedorn (NPH), on as many days, while controls were injected with diluent alone. Animals injected with four doses of
insulin were pretreated by i.c.v. administration of graded doses of the
glucocorticoid receptor antagonist or vehicle alone prior to the first three doses of
insulin. Repeated daily injection of NPH exacerbated
hypoglycemia, attenuated patterns of
glucagon and
epinephrine secretion, and diminished neuronal transcriptional activation in discrete CNS metabolic loci, including the lateral hypothalamic area, dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus, and nucleus of the solitary tract. While i.c.v. delivery of 25 or 100 ng doses of
CP-472555 did not alter any of these parameters, animals treated with 500 ng exhibited circulating
glucose,
glucagon, and
epinephrine levels that were similar to those in rats injected with one dose of
insulin, as well as a reversal of recurring
insulin-induced
hypoglycemia-associated reductions in Fos immunolabeling in the lateral hypothalamic area, dorsomedial hypothalamic nucleus, and paraventricular hypothalamic nucleus. These results provide unique pharmacological evidence that antecedent activation of central
glucocorticoid receptor is required for exacerbation of
hypoglycemia during recurring
insulin-induced
hypoglycemia, and that these receptors mediate modulatory effects of
hypoglycemic hypercorticosteronemia on autonomic efferent responses to recurring
insulin-induced
hypoglycemia. The data also suggest that neurons in central loci characterized here by antagonist-mediated overturn of recurring
insulin-induced
hypoglycemia-induced decreases in neuronal transcriptional activation may be direct or indirect substrates for this hormonal modulation action.