Prolonged hyperglucagonemia causes only a transient increase in hepatic glucose production. To determine whether activation of hepatic phosphodiesterase by glucagon is responsible for the transient nature of this response, the effect of infusion of the phosphodiesterase inhibitor theophylline alone, glucagon alone, and glucagon plus theophylline on isotopically determined glucose production was examined in normal human subjects. Infusion of theophylline alone did not alter rates of glucose production or utilization. Infusion of glucagon alone increased glucose production transiently from a basal rate of 1.9 +/- 0.1 mg/kg/min to a maximum at min 30 of 2.8 +/- 0.3 mg/kg/min followed by a return to rates no different from basal by min 60; plasma glucose increased from 89 +/- 3 mg/dl to a maximum of 114 +/- 5 mg/dl. Infusion of glucagon in the presence of theophylline resulted in greater increases in both plasma glucose (maximum at min 60 of 134 +/- 9 mg/dl) and glucose production (maximum at min 30 of 3.5 +/- 0.3 mg/kg/min) than had occurred during infusion of glucagon alone; the increase in glucose production, however, was not sustained. Thus theophylline potentiated glucagon-induced stimulation of hepatic glucose production, but it did not prevent the evanescent hepatic response to sustained hyperglucagonemia. Therefore, the present studies indices that glucagon activation of hepatic phosphodiesterase does not appear to be responsible for the transient nature of the increase in hepatic glucose production observed during prolonged hyperglucagonemia.