Effect of Ovine Corticotropin-Releasing Hormone Administered During Insulin-Induced Hypoglycemia on Plasma Adrenocorticotropin and Cortisol*

The factors that mediate the hypothalamic-pituitary response to hypoglycemia in man are unknown. To investigate the role of CRH in the plasma ACTH response to hypoglycemia, two different doses of ovine CRH (oCRH) were given to normal men during insulin-induced hypoglycemia. We hypothesized that if the endogenous CRH response to hypoglycemia were less than maximally stimulating, administration of oCRH during hypoglycemia would result in a greater peak plasma immunoreactive (IR) ACTH response. Six normal men were given 1) 0.15 U/kg regular insulin, iv; 2) insulin plus 1 μg/kg oCRH, iv, 5 min after serum glucose fell to 40 mg/dL or less; and 3) oCRH alone. The degree and duration of hypoglycemia were the same when insulin was given alone or with oCRH. Plasma IR-ACTH after insulin alone and insulin plus oCRH rose at the same rate to similar peaks of 226 ± 37 (mean ± sem) and 213 ± 53 pg/mL, respectively, both of which were greater (P < 0.05) than the peak plasma IR-ACTH after oCRH alone (61 ± 19 pg/mL). The peak plasma IR-cortisol levels after insulin alone (24 ± 4 μg/dL), insulin plus oCRH (27 ± 3 μg/dL), and oCRH alone (18 ± 2 μg/dL) were not significantly different. In a second study, six normal men were given 1) 0.15 U/kg regular insulin, iv; 2) insulin plus 10 μg/kg oCRH, iv; and 3) 10 μg/kg oCRH alone. Administration of oCRH 5 min after serum glucose fell to 40 mg/dL or less did not affect the degree or duration of hypoglycemia. Plasma IR-ACTH after insulin alone and insulin plus oCRH rose at the same rate to similar peaks of 258 ± 14 and 290 ± 33 pg/mL, respectively, both of which were greater (P < 0.01) than the peak (54 ± 6 pg/mL) after oCRH alone. After insulin alone, plasma IR-ACTH declined to baseline by 3 h. However, after insulin plus oCRH, plasma IR-ACTH fell gradually until 2 h, rose to a second peak at 2.5–3 h, and remained greater (P < 0.01) than after insulin or oCRH alone for the 4-h duration of the study. The mean peak plasma IRcortisol level after insulin plus oCRH (33 ± 4 μg/dL) was similar to that after insulin alone (28 ± 3 μg/dL), but was greater (P < 0.05) than that after oCRH alone (18 ± 2 μg/dL). These results demonstrate that 1) hypoglycemia causes a 4- to 5-fold greater plasma IR-ACTH response than does 1 or 10 μg/kg oCRH; 2) oCRH given at the onset of insulin-induced hypoglycemia does not increase the peak plasma IR-ACTH response to hypoglycemia, but 3) insulin plus 10 μg/kg oCRH results in a prolonged plasma IR-ACTH response that is greater than after either agent alone. These data suggest that the pituitary receives maximal stimulation from endogenous CRH during hypoglycemia, and that an agent or mechanism induced by hypoglycemia potentiates the prolonged plasma IR-ACTH response to exogenous oCRH (10 μg/kg).