ENDOTHELIN-1 INFUSION INHIBITS PLASMA-INSULIN RESPONSIVENESS IN NORMAL MEN

Objectives Elevated plasma endothelin (ET)-1 levels have been describe d in insulin-resistant states such as syndrome X, obesity, non-insulin -dependent diabetes mellitus, and in some studies in essential hyperte nsion. To investigate whether increases in circulating ET-1 to levels observed in insulin-resistant states can modulate insulin levels and/o r insulin sensitivity in humans, we assessed these variables during lo w, non-presser-dose ET-1 compared with placebo infusion. Design In a r andomized, single blind, crossover design, 10 lean normotensive male s ubjects 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 wit h the modified frequent sampling intravenous glucose tolerance test (F SIGT) the following and other parameters were measured: insulin sensit ivity; acute insulin response to glucose (AIR(G)) calculated as the av erage of the three peak values between 2 and 5 min after injection of glucose from which the basal insulin levels were substracted; the init ial area under the curve (AUC(1-19)) from insulin values between time 0 and 19 min and the first-phase insulin secretion (phi(1)) from insul in kinetics parameters. Results ET-1 infusion reduced AIR(G) (to 34.85 +/- 4.27 compared with 49.3 +/- 6.9 mu U/ml during placebo, P = 0.017 ) and the acute C-peptide response to glucose (to 2.33 +/- 0.41 compar ed with 3.1 +/- 0.44 ng/ml, P = 0.018), decreased plasma insulin level s during the FSIGT compared with placebo (analysis of variance P< 0.00 01) and decreased the AUC(1-19) (to 2.1 +/- 0.2 compared with 2.9 +/- 0.3 U/l per 20 min, P< 0.01) while phi(1) tended to be lower. S-I meas ured during ET-1 infusion was unaltered (11.11 +/- 1.91 x 10(-4) versu s 10.88 +/- 2.11 10(-4)/min per mU per I, NS). Conclusions These findi ngs demonstrate that an increase in circulating ET-1 to levels observe d in insulin-resistant states acutely diminishes the insulin secretory response but does not significantly modify insulin sensitivity. J Hyp ertens 16:1279-1284 (C) 1998 Lippincott Williams & Wilkins.