To ascertain whether small elevations of epinephrine alter glucose tolerance, we infused epinephrine or saline into seven healthy volunteers for 5 hours. Two hours after starting the infusions, subjects ingested 100 g of glucose. Plasma epinephrine (basal 23 +/- 4 pg/mL) rose during epinephrine infusion to levels (75 to 80 pg/mL) similar to those observed in nine outpatients presenting with mild viral illnesses (66 +/- 8 pg/mL). Although epinephrine produced only a small (5 mg/dL) increase n plasma glucose before glucose ingestion, after oral glucose the levels of glucose increased by 30 to 60 mg/dL above saline control values (163 +/- 14 mg/dL versus 108 +/- 15 at 2 h, p < 0.005). This diabetogenic effect occurred despite two-fold higher insulin levels and normal suppression of plasma glucagon. We conclude that small physiologic increments of epinephrine, which cause minimal changes in fasting plasma glucose, produce a marked reduction in glucose tolerance. Our data suggest marked sensitivity to the insulin antagonistic effects of epinephrine and may provide a mechanism for stress-induced glucose intolerance.