title: The bilirubin-increasing drug atazanavir improves endothelial function in patients with type 2 diabetes mellitus.
abstract: OBJECTIVE
  In type 2 diabetes mellitus (T2DM), oxidative stress gives rise to endothelial dysfunction. Bilirubin, a powerful endogenous antioxidant, significantly attenuates endothelial dysfunction in preclinical experiments. The Gilbert syndrome is accompanied by a mild and lifelong hyperbilirubinemia and associated with only one third of the usual cardiovascular mortality risk. The hyperbilirubinemia caused by atazanavir treatment closely resembles the Gilbert syndrome. We thus hypothesized that treatment with atazanavir would ameliorate oxidative stress and vascular inflammation and improve endothelial function in T2DM.
  
  
  RESULTS
  In a double-blind, placebo-controlled crossover design, we induced a moderate hyperbilirubinemia by a 3-day atazanavir treatment in 16 subjects experiencing T2DM. On the fourth day, endothelial function was assessed by venous occlusion plethysmography. Endothelium-dependent and endothelium-independent vasodilation were assessed by intraarterial infusion of acetylcholine and nitroglycerin, respectively. Atazanavir treatment induced an increase in average bilirubin levels from 7 μmol/L (0.4 mg/dL) to 64 μmol/L (3.8 mg/dL). A significant improvement in plasma antioxidant capacity (P<0.001) and endothelium-dependent vasodilation (P=0.036) and a decrease in plasma von Willebrand factor (P=0.052) were observed.
  
  
  CONCLUSIONS
  Experimental hyperbilirubinemia is associated with a significant improvement of endothelial function in T2DM.
authors.affiliation: Radboud University Nijmegen Medical Centre, Nijimegen Center for Molecular Life Sciences, Departments of Pharmacology and Toxicology, and Orthodontics and Oral Biology, Nijmegen, the Netherlands.
authors.forename: Douwe
authors.initials: D
authors.lastname: Dekker
authors.forename: Mirrin J
authors.initials: MJ
authors.lastname: Dorresteijn
authors.forename: Margot
authors.initials: M
authors.lastname: Pijnenburg
authors.forename: Suzanne
authors.initials: S
authors.lastname: Heemskerk
authors.forename: Anja
authors.initials: A
authors.lastname: Rasing-Hoogveld
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.forename: Frank A D T G
authors.initials: FA
authors.lastname: Wagener
authors.forename: Paul
authors.initials: P
authors.lastname: Smits
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000069446:Atazanavir Sulfate; D001663:Bilirubin / Q000097:blood*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D011725:Pyridines; D014665:Vasodilator Agents; D014841:von Willebrand Factor; D000069446:Atazanavir Sulfate; D005996:Nitroglycerin; D000109:Acetylcholine; D001663:Bilirubin