Antecedent increases of corticosteroids can blunt counterregulatory responses to subsequent stress. Our aim was to determine if prior activation of type I corticosteroid (mineralocorticoid) or type II corticosteroid (glucocorticoid) receptors blunts counterregulatory responses to subsequent hypoglycemia. Healthy volunteers participated in 5 randomized two-day protocols. Day 1 involved morning and afternoon 2 h hyperinsulinemic (9 pmol·kg-1·min-1) euglycemic clamps (PE; n=14), hypoglycemic clamps (PH; n=14), or euglycemic clamps with oral fludrocortisone (PE+F; type I agonist; 0.2 mg; n=14), or oral dexamethasone (PE+D; type II agonist; 0.75 mg; n=13), or both (PE+F+D; n=14). Day 2 was identical in all protocols and consisted of a 2 h hyperinsulinemic hypoglycemic clamp. Day 2 insulin (625 40 pmol/l) and glucose (2.9 0.1 mmol/l) levels were similar among groups. Levels of epinephrine, norepinephrine, glucagon, growth hormone and muscle sympathetic nerve activity were significantly blunted by prior activation of both type I and type II corticosteroid receptors to PE. Prior activation of both corticosteroid receptors also significantly blunted nonesterified fatty acids during subsequent hypoglycemia. Thus, levels of a wide spectrum of key counterregulatory mechanisms (neuroendocrine, autonomic nervous system and metabolic) were blunted by antecedent pharmacologic stimulation of either type I or type II corticosteroid receptors in healthy man. These data suggest that activation of type I corticosteroid receptors in man can have acute and profound regulating effects on physiologic stress in man. Both type I and type II corticosteroid receptors may be involved in the multiple mechanisms controlling counterregulatory responses to hypoglycemia in healthy man.