Prostaglandin synthesis inhibitors impair hepatic glucose production in response to glucagon and epinephrine stimulation.

To investigate whether inhibition of prostaglandin synthesis affects hormone-induced glucose dynamics, we measured glucose turnover in response to glucagon alone (5 ng . kg-1 min-1) or combined with epinephrine (0.1 microgram . kg-1 min-1) in conscious trained dogs (N = 6) on three separate occasions in each animal: (1) during a control saline infusion, (2) during infusion of indomethacin, and (3) during infusion of sodium salicylate. Glucose production (Ra) and utilization (Rd) were determined by isotope dilution using the nonrecycling label 3-3H glucose. In controls, glucagon levels (IRG) rose from a basal of 44 +/- 12 to 260 +/- 40 pg/ml (mean +/- SEM) during glucagon infusion; basal epinephrine levels (EPI) of 150 +/- 20 pg/ml were unaffected by glucagon infusion but rose four- to fivefold during combined glucagon/epinephrine infusion. Plasma glucose rose transiently from 95 +/- 1 to a peak of 136 +/- 13 mg/dl after 20 min of glucagon; infusion of EPI resulted in a second glycemic response with a peak of 148 +/- 9 mg/dl. Ra increased transiently from 2.9 +/- 0.2 to a peak of 7.9 +/- 1.4 mg . kg-1 min-1 during glucagon alone with a second rise to 6.2 +/- 0.8 mg . kg-1 min-1 10 min after beginning EPI. With glucagon alone, Rd paralleled Ra but addition of EPI resulted in a relative fall in Rd. Insulin (IRI) rose from 9 +/- 1 microU/ml to 29 +/- 6 microU/ml with glucagon but IRI fell despite the second glycemic response during EPI. When either indomethacin or salicylate was infused, basal IRI, IRG, EPI, glucose, Ra and Rd were unaffected and were similar to controls. Although plasma levels of IRG and EPI during glucagon or glucagon plus epinephrine infusion were also similar to controls, the glycemic response was reduced (P less than 0.05). This attenuation of glycemic response was due to a reduction of stimulated Ra (P less than 0.05) and not to an increase in Rd. Changes in IRI paralleled the reduction in glycemic response. Thus, both indomethacin and salicylate blunt the glycemic response to glucagon and glucagon plus epinephrine by attenuating glucose production and not by enhancing glucose utilization or insulin secretion. These results with two prostaglandin synthesis inhibitors suggest that prostaglandins modulate the hepatic effects of glucagon and epinephrine.