title: Exogenous endothelin-1 causes peripheral insulin resistance in healthy humans.
abstract: In states 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-1 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-1 (4 pmol kg-1 min-1) or 0.9% sodium chloride. During the endothelin-1 infusion, arterial plasma endothelin-1 levels rose 10-fold. The endothelin-1 infusion reduced insulin sensitivity as demonstrated by a 31 +/- 7% decrease in whole-body glucose uptake (P < 0.05) and a 26 +/- 11% fall in leg glucose uptake (P < 0.05) compared with the control protocol. During the state of hyperinsulinaemia, exogenous endothelin-1 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-1 infusion did not lower skeletal muscle blood flow measured as leg and forearm blood flow. In summary, exogenous endothelin-1 induced insulin resistance in healthy humans by reducing insulin-dependent glucose uptake in skeletal muscle without decreasing skeletal muscle blood flow. Furthermore, endothelin-1 also preserved its vasoactive potency in the presence of hyperinsulinaemia.
authors.affiliation: Department of Clinical Science, Huddinge University Hospital, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Ottosson-Seeberger
authors.forename: J M
authors.initials: JM
authors.lastname: Lundberg
authors.forename: A
authors.initials: A
authors.lastname: Alvestrand
authors.forename: G
authors.initials: G
authors.lastname: Ahlborg
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D004573:Electrolytes / Q000097:blood; D019332:Endothelin-1 / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008102:Liver Circulation / Q000187:drug effects / Q000502:physiology; D008111:Liver Function Tests; D008297:Male
chemical_list: D001786:Blood Glucose; D004573:Electrolytes; D019332:Endothelin-1; D007328:Insulin; D005947:Glucose