ROLE OF CORTISOL IN THE PATHOGENESIS OF DEFICIENT COUNTERREGULATION AFTER ANTECEDENT HYPOGLYCEMIA IN NORMAL HUMANS

The aim of this study was to determine the role of increased plasma co rtisol 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 ra ndomized 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 (5 3 +/- 2 mg/dl) or euglycemia (93 +/- 3 mg/dl) was obtained during morn ing and afternoon, The next morning subjects underwent a 2-h hyperinsu linemic (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 stimu late levels of plasma cortisol occurring during clamped hypoglycemia ( 53 mg/dl), The next morning (day 2) subjects underwent a 2-h hyperinsu linemic hypoglycemic clamp identical to the first group, Despite equiv alent day 2 plasma glucose and insulin levels, steady state epinephrin e, norepinephrine, pancreatic polypeptide, glucagon, ACTH and muscle s ympathetic nerve activity (MSNA) values were significantly (P < 0.01) blunted after day 1 cortisol infusion compared to antecedent euglycemi a. Compared to day 1 cortisol, antecedent hypoglycemia produced simila r blunted day 2 responses of epinephrine, norepinephrine, pancreatic p olypeptide and MSNA compared to day 1 cortisol, Antecedent hypoglycemi a, however, produced a more pronounced blunting of plasma glucagon, AC TH, and hepatic glucose production compared to day 1 cortisol. We conc lude that in healthy overnight fasted men (a) antecedent physiologic i ncreases of plasma cortisol can significantly blunt epinephrine, norep inephrine, glucagon, and MSNA responses to subsequent hypoglycemia and (b) these data suggest that increased plasma cortisol is the mechanis m responsible for antecedent hypoglycemia causing hypoglycemia associa ted autonomic failure.