Role of Corticotrophin-releasing Hormone in the Impairment of Counterregulatory Responses to Hypoglycemia

We have explored the role of individual elements of the hypothalamic pituitary adrenal axis on the pathogenesis of hypoglycemia-associated autonomic failure. Five groups of male Sprague-Dawley rats were used. Control animals had 3 days of sham treatment followed by a hyperinsulinemic/hypoglycemic glucose clamp on day 4. A second group underwent 3 days of antecedent insulin-induced hypoglycemia then a subsequent clamp. Three more groups underwent pretreatment with corticosterone, adrenocorticotrophic hormone (ACTH), or corticotrophin-releasing hormone (CRH) mirroring the glucocorticoid response of the hypoglycemic group. Subsequent counterregulatory responses showed marked differences. CRH- (and insulin-treated) animals showed markedly reduced epinephrine responses (CRH 1,276 +/- 404 pg/ml, controls 3,559 +/- 563 pg/ml; P < 0.05). In contrast, ACTH pretreatment augmented epinephrine responses (6,681 +/- 814 pg/ml; P = 0.007 versus controls); corticosterone pretreatment caused a similar but nonsignificant enhancement. The same pattern was seen for norepinephrine. CRH pretreatment also suppressed glucagon responses to hypoglycemia (control 157 +/- 21, CRH 68 +/- 10 pg/ml; P = 0.004). The addition of a CRH receptor 1 (CRHr1) antagonist to the antecedent CRH reversed the subsequent suppression of epinephrine. These findings suggest that CRH acting via CRHr1 plays an important role in the sympathoadrenal downregulation seen in this rodent model of antecedent hypoglycemia; this action is not mediated via activation of the hypothalamic-pituitary-adrenal axis.