Infusion of prostaglandin E2 (PGE2) has been previously shown to inhibit acute insulin release and cause glucose intolerance. The present studies were undertaken to assess the effects of PGE2 on 1) pancreatic beta-cell sensitivity to glucose, 2) glucose tolerance, 3) tissue sensitivity to insulin, 4) glucose production and clearance, and 5) plasma catecholamine, glucagon, and FFA levels. Six healthy adult subjects were studied with the hyperglycemic clamp technique (plasma glucose 125 mg/dl above basal for 2 h) before and 30 min after the start of a PGE2 infusion (10 micrograms/min). Plasma epinephrine, norepinephrine, and FFA were measured during the PGE2 infusion. In additional experiments, glucose production and utilization were measured isotopically ([3-3H]glucose) during PGE2 infusion. PG infusion diminished, but not significantly, acute insulin release (0-10 min preinfusion, 172 +/- 36; postinfusion, 148 +/- 45 microunits/ml . 10 min). Late insulin release (20-120 min) was unchanged. A significant decline occurred in the amount of glucose metabolized from 9 +/- 1.1 to 7.2 +/- 1 mg/kg . min. During the initial 30 min of PGE2 infusion, plasma FFA increased by 26 +/- 6% (P less than 0.025). Plasma epinephrine and norepinephrine rose from 40 +/- 6 to 104 +/- 24 pg/ml (P less than 0.05) and 204 +/- 17 to 440 +/- 30 pg/ml (P less than 0.01), respectively. PGE2 produced a prompt 30% rise in glucose output, which declined to basal levels by 60 min. Glucose clearance decreased transiently at 45 min by 23%. We conclude that the effects on glucose homeostasis noted during PGE2 infusion occur in the face of heightened adrenergic activity. These metabolic responses closely resemble adrenergically induced changes in glucose homeostasis. As such, before any metabolic effects can be attributed directly to infused PGE2, any metabolic effects can be attributed directly to infused PGE2, the role of concomitant catecholamine release must be considered.