Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans

The aim of this study was to determine whether the duration of antecedent h ypoglycemia regulates the magnitude of subsequent counterregulatory failure . A total of 31 lean healthy overnight-fasted individuals (16 men/15 women) were studied. There were 15 subjects (8 men/7 women) who underwent two sep arate 2-day randomized experiments separated by at least 2 months. On day 1 , 2-h hyperinsulinemic (9 pmol . kg(-1) . min(-1)) euglycemic (5.2 +/- 0.1 mmol/l) or hypoglycemic (2.9 +/- 0.1 mmol/l) glucose clamps (prolonged hypo glycemia) were carried out in the morning and afternoon. Of the other subje cts, 16 participated in a 2-day study in which day 1 consisted of morning a nd afternoon short-duration hypoglycemia experiments (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 5 min), and 10 of these individuals underwent an addi tional 2-day study in which day 1 consisted of morning and afternoon interm ediate-duration hypoglycemia (hypoglycemic nadir of 2.9 +/- 0.1 mmol for 30 min). The next morning (day 2) all subjects underwent an additional 2-h hy perinsulinemic-hypoglycemic clamp (2.9 +/- 0.1 mmol/l), The rate of fall of glucose (0.07 mmol/min) was carefully controlled during all hypoglycemic s tudies so that the glucose nadir was reached at 30 min. Despite equivalent day 2 plasma glucose and insulin levels, there were significant differences in counterregulatory physiological responses. Steady-state epinephrine, gl ucagon, growth hormone, cortisol, and pancreatic polypeptide levels were si milarly significantly blunted (P < 0.01) by the differing duration day 1 hy poglycemia compared with day 1 euglycemia, Muscle sympathetic nerve activit y and endogenous glucose production were also similarly blunted (P < 0.01) by day 1 hypoglycemia (relative to day 1 euglycemia), Day 2 hypoglycemic sy mptoms were significantly reduced CP < 0.01) after day 1 prolonged intermed iate- but not short-duration hypoglycemia, In summary, two episodes of shor t-duration moderate hypoglycemia can produce significant blunting of key ne uroendocrine and metabolic counterregulatory responses. Hypoglycemic sympto m scores are reduced by prolonged but not short-duration prior hypoglycemia . We conclude that in healthy overnight fasted humans, 1) neuroendocrine, a utonomic nervous system, and metabolic counterregulatory responses are sens itive to the blunting effects of even short-duration prior hypoglycemia, an d 2) the duration of antecedent hypoglycemia results in a hierarchy of blun ted physiological responses with hypoglycemic symptom awareness less vulner able than neuroendocrine responses.