The rise and subsequent return to basal of glucose production (Ra) during a constant glucagon infusion ("downregulation") has suggested to some workers that glucagon's effects are evanescent. To examine whether glucagon displays persistent biological activity even after downregulation, 6 healthy males received an 8 hour infusion of somatostatin and glucagon, with 3H-3-glucose to measure glucose turnover. Ra rose from 2.8 +/- 0.3 to 4.2 +/- 0.3 mg/kg . min at 90 minutes, returned to basal levels at 150 minutes, and remained at this level for the ensuing 330 minutes. Six additional subjects received an 8 hour somatostatin infusion, with glucagon administered concomitantly for the first 5 hours. Glucagon withdrawal at 5 hours produced an immediate decline in Ra from 1.8 +/- 0.2 to 0.9 +/- 0.2 mg/kg . min. Thus, even after downregulation the maintenance of basal Ra is dependent on circulating glucagon.