The aim of this study was to determine whether preventing increases in plasma
cortisol during antecedent
hypoglycemia preserves autonomic nervous system counterregulatory responses during subsequent
hypoglycemia. Experiments were carried out on 15 (8 male/7 female) healthy, overnight-fasted subjects and 8 (4 male/4 female) age- and weight-matched patients with primary adrenocortical failure. 5 d before a study, patients had their usual
glucocorticoid therapy replaced with a continuous
subcutaneous infusion of
cortisol programmed to produce normal daily circadian levels. Both groups underwent identical 2-d experiments. 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) was obtained during the morning and afternoon. The next morning, subjects underwent an additional 2-h
hypoglycemic (53+/-2 mg/ dl) hyperinsulinemic clamp. In controls, day 2 steady state
epinephrine,
norepinephrine,
pancreatic polypeptide,
glucagon,
growth hormone, and muscle sympathetic nerve activity were significantly blunted (P < 0.01) compared with day 1
hypoglycemia. In marked contrast, when increases of plasma
cortisol were prevented in the patient group, day 2 neuroendocrine, muscle sympathetic nerve activity,
hypoglycemic symptoms, and metabolic counterregulatory responses were equivalent with day 1 results. We conclude that (a) prevention of increases of
cortisol during antecedent
hypoglycemia preserves many critical autonomic nervous system counterregulatory responses to subsequent
hypoglycemia; (b)
hypoglycemia-induced increases in plasma
cortisol levels are a major mechanism responsible for causing subsequent
hypoglycemic counterregulatory failure; and (c) our results suggest that other mechanisms, apart from
cortisol, do not play a major role in causing
hypoglycemia-associated autonomic failure.