Antecedent hypercortisolemia is not primarily responsible for generating hypoglycemia-associated autonomic failure.

Hypoglycemia-associated autonomic failure (HAAF) occurs commonly in patients with longstanding diabetes, placing affected patients at increased risk for severe hypoglycemia. Previous studies have suggested that hypoglycemia-induced hypercortisolemia may be responsible for blunting subsequent sympathoadrenal responses to hypoglycemia; however, this view remains highly controversial. In this work, we sought to better define the role of antecedent hypercortisolemia in generating HAAF, using two complimentary experimental models in nondiabetic human subjects: 1) antecedent hydrocortisone infusions (simulating physiologic cortisol responses to hypoglycemia) and 2) antecedent hypoglycemia, with and without concurrent blockade of endogenous cortisol production using oral metyrapone.