In man prolonged infusions of glucagon cause a transient increase in glucose production. To determine whether this represents complete loss of effect of hyperglucagonemia on the liver or merely decreased hepatic responsiveness, glucagon (3 ng/kg/min) was infused in six normal subjects to produce sustained hyperglucagonemia for 180 min; at this time glucagon infusions were stopped for 60 min, then restarted at the same rate for 60 min and finally increased to 7.5 ng/kg/min for 30 min. Glucose production (Ra) and utilization (Rd) were measured isotopically. Initially glucagon infusion increased Ra transiently from 1.8 +/- 0.1 mg/kg/min to a maximum at 15 min of 2.5 +/- 0.2 mg/kg/min (p less than .01); Ra returned to basal values by 60 min and remained there until the glucagon infusion was stopped, whereupon it abruptly declined to a nadir of 1.4 +/- 0.1 mg/kg/min, a value significantly below baseline levels, p less than .005. Upon restarting the glucagon infusion, Ra increased to a similar extent as observed with the initial infusion and then returned to basal levels; when the glucagon infusion rate was increased to 7.5 ng/kg/min, Ra again increased. These results indicate that sustained hyperglucagonemia, despite apparent waning of its effect, continues to modulate hepatic glucose production.