The aim of this study was to determine the role of increased plasma
cortisol levels in the pathogenesis of
hypoglycemia-associated autonomic failure. Experiments were carried out on 16 lean, healthy, overnight fasted male subjects. One group (n = 8) underwent two separate, 2-d randomized experiments separated by at least 2 mo. On day 1
insulin was infused at a rate of 1.5 mU/kg per min and 2 h clamped
hypoglycemia (53 +/- 2 mg/dl) or euglycemia (93 +/- 3 mg/dl) was obtained during morning and afternoon. The next morning subjects underwent a 2-h hyperinsulinemic (1.5 mU/kg per min)
hypoglycemic (53 +/- 2 mg/dl) clamp study. In the other group (n = 8), day 1 consisted of morning and afternoon 2-h clamped hyperinsulinemic euglycemia with
cortisol infused to stimulate levels of plasma
cortisol occurring during clamped
hypoglycemia (53 mg/dl). The next morning (day 2) subjects underwent a 2-h hyperinsulinemic
hypoglycemic clamp identical to the first group. Despite equivalent day 2 plasma
glucose and
insulin levels, steady state
epinephrine,
norepinephrine,
pancreatic polypeptide,
glucagon,
ACTH and muscle sympathetic nerve activity (MSNA) values were significantly (R < 0.01) blunted after day 1
cortisol infusion compared to antecedent euglycemia. Compared to day 1
cortisol, antecedent
hypoglycemia produced similar blunted day 2 responses of
epinephrine,
norepinephrine,
pancreatic polypeptide and MSNA compared to day 1
cortisol. Antecedent
hypoglycemia, however, produced a more pronounced blunting of plasma
glucagon,
ACTH, and hepatic
glucose production compared to day 1
cortisol. We conclude that in healthy overnight fasted men (a) antecedent physiologic increases of plasma
cortisol can significantly blunt
epinephrine,
norepinephrine,
glucagon, and MSNA responses to subsequent
hypoglycemia and (b) these data suggest that increased plasma
cortisol is the mechanism responsible for antecedent
hypoglycemia causing
hypoglycemia associated autonomic failure.