OBJECTIVE To assess the effect of oral glucose loading on plasma endothelin-1 (ET-1) levels in humans. RESEARCH DESIGN AND METHODS A total of 75 g D-glucose was given orally to 14 nonobese nondiabetic essential hypertensive subjects (eight men and six women, mean age 43.1 ± 3.0 years) and eight normotensive subjects (four men and four women, mean age 45.2 ± 4.1 years). Blood samples for plasma ET-1 measurement were drawn every 30 min for 2 h and then at 180 and 240 min. RESULTS After glucose load, insulin increased more significantly in hypertensive subjects than in normotensive subjects at times 60 (P = 0.004) and 90 (P = 0.001) min. Glucose loading was followed by a mild but significant increase in circulating ET-1 levels in both groups (hypertensive subjects, from 0.87 ± 0.25 pg/ml at time 0 to 1.64 ± 0.33 pg/ml at 120 min and 1.74 ± 0.38 pg/ml at 180 min, P < 0.05; normotensive subjects, from 0.82 ± 0.38 pg/ml at time 0 to 1.42 ± 0.18 pg/ml at 180 min, P < 0.05). Whereas baseline ET-1 levels were similar between the two groups, postload ET-1 levels were higher in hypertensive subjects than in normotensive subjects (P = 0.003 at 120 min; P = 0.04 at 180 min). CONCLUSIONS This study indicates that significant changes in circulating ET-1 levels occur after oral glucose loading, probably due to a glucose-induced increment in endogenous insulin concentration.