The present investigation was undertaken to characterize glucagon responses to hypoglycemia in man. Using a highly specific antiserum, plasma immunoreactive glucagon levels were determined during episodes of insulininduced hypoglycemia in 15 normal subjects and during oral glucose tolerance tests in 4 subjects with reactive hypoglycemia. During insulininduced hypoglycemia, plasma glucagon rose from a mean (±sem) basal level of 143 ± 6.5 pg/ml to a maximum of 471 ± 15 pg/ml at 45 min, p <. 001. Initial glucagon responses were evident 15 min after insulin administration and precedes those of cortisol and growth hormone. Total glucagon responses (area under curve) correlated positively with the total decrease in plasma glucose (area below basal), r = 0.852, p < 0.0005, rather than the nadir or absolute level of hypoglycemia achieved. Hyperglycemia induced by 60 min glucose infusions, which suppressed glucagon secretion, did not prevent glucagon responses to subsequent insulin-induced hypoglycemia. Moreover the fall in plasma glucose from a mean of 187 mg/100 ml to 112 mg/100 ml was sufficient to stimulate glucagon secretion. In all subjects with reactive hypoglycemia plasma glucagon rose at least 2 times basal.

Thus, in man, hypoglycemia is a potent stimulus for glucagon secretion. The rate of fall of plasma glucose as well as the degree and duration of hypoglycemia are important determinants of the glucagon response. These findings suggest that pancreatic glucagon may function physiologically as a hypoglycemic counter-regulatory hormone, and that glucagon responses to hypoglycemia may provide an additional parameter with which to assess pancreatic alpha cell function in man.