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Elevated plasma endothelin (ET)-1 levels have been described in insulin-resistant states such as syndrome X, obesity, non-insulin-dependent diabetes mellitus, and in some studies in essential hypertension. To investigate whether increases in circulating ET-1 to levels observed in insulin-resistant states can modulate insulin levels and/or insulin sensitivity in humans, we assessed these variables during low, non-pressor-dose ET-1 compared with placebo infusion.In a randomized, single blind, crossover design, 10 lean normotensive male subjects received either an intravenous infusion of subpressor doses of ET-1 dissolved in polygeline or a control infusion of polygeline only (placebo). Using dynamic assessment by the minimal model approach with the modified frequent sampling intravenous glucose tolerance test (FSIGT) the following and other parameters were measured: insulin sensitivity; acute insulin response to glucose (AIRG) calculated as the average of the three peak values between 2 and 5 min after injection of glucose from which the basal insulin levels were substracted; the initial area under the curve (AUC1-19) from insulin values between time 0 and 19 min and the first-phase insulin secretion (φ1) from insulin kinetics parameters.ET-1 infusion reduced AIRG (to 34.85 ± 4.27 compared with 49.3 ± 6.9 μU/ml during placebo, P = 0.017) and the acute C-peptide response to glucose (to 2.33 ± 0.41 compared with 3.1 ± 0.44 ng/ml, P = 0.018), decreased plasma insulin levels during the FSIGT compared with placebo (analysis of variance P < 0.0001) and decreased the AUC1-19 (to 2.1 ± 0.2 compared with 2.9 ± 0.3 U/l per 20 min, P < 0.01) while f1 tended to be lower. SI measured during ET-1 infusion was unaltered (11.11 ± 1.91 × 10-4 versus 10.88 ± 2.11 10-4/min per mU per l, NS).These findings demonstrate that an increase in circulating ET-1 to levels observed in insulin-resistant states acutely diminishes the insulin secretory response but does not significantly modify insulin sensitivity.