Exogenous endothelin-1 causes peripheral insulin resistance in healthy humans

In slates of insulin resistance, increased plasma levels of endothelin-1 and a disturbed vascular reactivity have been reported. In order to investigate the effects of endothelin-l on peripheral insulin sensitivity and the vasoactive interactions between insulin and endothelin-1, six healthy subjects were studied on two different occasions with the euglycaemic hyperinsulinaemic clamp technique combined with an intravenous infusion of either endothelin-l (4 pmol kg(-1) min(-1)) or 0.9% sodium chloride. During the endothelin-l infusion, arterial plasma endothelin-l levels rose 10-fold. The endothelin-l infusion reduced insulin sensitivity as demonstrated by a 31 +/- 7% decrease in whole-body glucose uptake (P < 0.05) and a 26 +/- 11% fail in leg glucose uptake (P < 0.05) compared with the control protocol. During the state of hyperinsulinaemia, exogenous endothelin-l increased mean arterial blood pressure by 8 +/- 1% (P < 0.05) and decreased splanchnic and renal blood flow by 30 +/- 6% (P < 0.001) and 20 +/- 4% (P < 0.001), respectively. However, the endothelin-l infusion did not lower skeletal muscle blood flow measured as leg and forearm blood flow. In summary, exogenous endothelin-l induced insulin resistance in healthy humans by reducing insulin-dependent glucose uptake in skeletal muscle without decreasing skeletal muscle blood flow. Furthermore, endothelin-l also preserved its vasoactive potency in the presence of hyperinsulinaemia.