EFFECTS OF DIFFERING ANTECEDENT HYPOGLYCEMIA ON SUBSEQUENT COUNTERREGULATION IN NORMAL HUMANS

The aim of the study was to determine the effects of specific levels o f antecedent hypoglycemia on subsequent autonomic, neuroendocrine, and metabolic counterregulatory responses. Eight healthy, overnight-faste d male subjects were studied during a-day protocols on four separate r andomized occasions separated by at least 2 months. On day 1, insulin was infused at a rate of 9 pmol.kg(-1).min(-1) and 2-h clamped euglyce mia (plasma glucose 5.2 +/- 0.2 mmol/l) or differing hypoglycemia (pla sma glucose 3.9 +/- 0.1, 3.3 +/- 0.1, or 2.9 +/- 0.1 mmol/l) was obtai ned during morning and afternoon. The next morning after an evening me al and 10-h overnight fast, each subject underwent a 2-h hyperinsuline mic (9 pmol.kg(-1).min(-1)) hypoglycemic (2.9 +/- 0.1 mmol/l) clamp st udy. Despite equivalent day 2 plasma glucose and insulin levels, diffe ring levels of antecedent hypoglycemia produced specific blunting of s ubsequent counterregulatory responses. Day 1 hypoglycemia of 3.9 mmol/ l resulted in significantly (P < 0.01) blunted epinephrine, muscle sym pathetic nerve activity, and glucagon responses. Day 1 hypoglycemia of 3.3 mmol/l resulted in additional significant blunting (P < 0.01) of pancreatic: polypeptide, norepinephrine, growth hormone, endogenous gl ucose production, and lipolytic responses. Deeper day 1 hypoglycemia o f 2.9 mmol/l produced similar day 2 counterregulatory failure as day 1 hypoglycemia of 3.3 mmol/l. In summary, in healthy overnight-fasted m en, mild antecedent hypoglycemia of 3.9 mmol/l significantly blunts sy mpathoadrenal and glucagon, but not other forms of neuroendocrine coun terregulatory responses, to subsequent hypoglycemia. Antecedent hypogl ycemia of 3.3 mmol/l resulted in additional significant blunting of al l major neuroendocrine and metabolic responses to subsequent hypoglyce mia. We conclude that in normal humans, there is a hierarchy of blunte d counterregulatory responses that are determined by the depth of ante cedent hypoglycemia.