Inhibition of glucagon-induced hepatic glucose production by indomethacin

We investigated the effects of indomethacin on plasma glucose and insulin, hepatic glucose output (Ra), and glucose utilization (Rd) during constant glucagon infusion in intact, anesthetized postabsorptive rats. Glucagon infusion at 5 ng/(kg.min) for 2 h achieved concentrations in plasma of 375-580 pg/ml in all animals. In normal rats plasma glucose rose from 114 ± 3 mg/dl (mean ± SE) to 134 ± 4 mg/dl within 5 min (P < 0.01); values remained elevated for 90 min and then declined to basal by 120 min. Plasma insulin concentrations also increased transiently. Ra, determined during infusion of [2-³H]glucose, increased briefly after starting glucagon, but returned to basal by 15 min. Indomethacin had no effect on plasma glucose, insulin, and glucagon concentrations or Ra prior to or during a saline infusion. However, the same dose of indomethacin markedly attenuated the early plasma glucose and insulin responses to glucagon (P < 0.05) and augmented the subsequent rate of fall in glucose and insulin so that values were significantly below basal during the 2nd h of glucagon infusion. These changes in plasma glucose were due to marked attenuation of glucagon-induced Ra. Liver glycogen content was similar in indomethacin-treated and untreated groups. Infusion of PGE₁ (10 ng/min) into the portal vein prevented the marked fall in peripheral glucose during the 2nd h of glucagon infusion in indomethacin-treated animals, but did not restore the initial glycemic response. Thus, in the rat, during constant glucagon infusion hepatic glucose output increases only transiently, indomethacin markedly inhibits hepatic glucose output and results in blood glucose values below basal during the 2nd h, and PGE₁ prevents this late fall in blood glucose.