title: Endothelin-1 reduces glucose uptake in human skeletal muscle in vivo and in vitro.
abstract: OBJECTIVE
  Endothelin (ET)-1 is a vasoconstrictor and proinflammatory peptide that may interfere with glucose uptake. Our objective was to investigate whether exogenous ET-1 affects glucose uptake in the forearm of individuals with insulin resistance and in cultured human skeletal muscle cells.
  
  
  METHODS
  Nine male subjects (aged 61 ± 3 years) with insulin resistance (M value <5.5 mg/kg/min or a homeostasis model assessment of insulin resistance index >2.5) participated in a protocol using saline infusion followed by ET-1 infusion (20 pmol/min) for 2 h into the brachial artery. Forearm blood flow (FBF), endothelium-dependent vasodilatation, and endothelium-independent vasodilatation were assessed. Molecular signaling and glucose uptake were determined in cultured skeletal muscle cells.
  
  
  RESULTS
  ET-1 decreased forearm glucose uptake (FGU) by 39% (P < 0.05) after the 2-h infusion. ET-1 reduced basal FBF by 36% after the 2-h infusion (P < 0.05) and impaired both endothelium-dependent vasodilatation (P < 0.01) and endothelium-independent vasodilatation (P < 0.05). ET(A) and ET(B) receptor expression was detected on cultured skeletal muscle cells. One-hour ET-1 incubation increased glucose uptake in cells from healthy control subjects but not from type 2 diabetic patients. Incubation with ET-1 for 24 h reduced glucose uptake in cells from healthy subjects. ET-1 decreased insulin-stimulated Akt phosphorylation and increased phosphorylation of insulin receptor substrate-1 serine 636.
  
  
  CONCLUSIONS
  ET-1 not only induces vascular dysfunction but also acutely impairs FGU in individuals with insulin resistance and in skeletal muscle cells from type 2 diabetic subjects. These findings suggest that ET-1 may contribute to the development of insulin resistance in skeletal muscle in humans.
authors.affiliation: Department of Medicine, Division of Cardiology, Karolinska Institute, Stockholm, Sweden. alexey.shemyakin@ki.se
authors.forename: Alexey
authors.initials: A
authors.lastname: Shemyakin
authors.forename: Firoozeh
authors.initials: F
authors.lastname: Salehzadeh
authors.forename: Daniella
authors.initials: D
authors.lastname: Esteves Duque-Guimaraes
authors.forename: Felix
authors.initials: F
authors.lastname: Böhm
authors.forename: Eric
authors.initials: E
authors.lastname: Rullman
authors.forename: Thomas
authors.initials: T
authors.lastname: Gustafsson
authors.forename: John
authors.initials: J
authors.lastname: Pernow
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
mesh_terms: D000368:Aged; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology*; D005542:Forearm / Q000098:blood supply; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D019332:Endothelin-1; D005947:Glucose