title: Insulinotropic compounds decrease endothelial cell survival.
abstract: OBJECTIVE
  Hyperglycemia induces damage of vascular endothelial cells leading to diabetic complications. We investigated the effects of insulinotropic compounds and elevated glucose on endothelial cells in the absence or presence of vascular endothelial growth factor (VEGF).
  
  
  RESULTS
  Human umbilical vein endothelial cells (HUVECs) were treated with glibenclamide, repaglinide and insulinotropic imidazolines at high glucose concentration in the presence or absence of VEGF and viability, proliferation and nitric oxide production were measured. Hyperglycemia inhibited pro-survival effects of VEGF on endothelial cells. Glibenclamide and repaglinide decreased HUVEC viability at elevated glucose concentration in the absence but not in the presence of VEGF, without affecting HUVEC proliferation. Repaglinide also had some positive influence on HUVEC function elevating NO production in the presence of VEGF. Imidazolines showed different activities on endothelial cell survival. Efaroxan diminished HUVEC viability at elevated glucose concentration in the presence, however not in the absence of VEGF, while RX871024 decreased HUVEC survival regardless of the presence of VEGF.
  
  
  CONCLUSIONS
  Our data demonstrate an important interplay between the actual insulinotropic compounds, VEGF and ambient glucose concentration affecting the survival of the vascular endothelial cells. Consequently, this interplay needs to be taken into consideration when designing novel oral antidiabetic compounds.
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors.forename: Irina I
authors.initials: II
authors.lastname: Zaitseva
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-17176 Stockholm, Sweden; Lomonosov Moscow State University, Belozersky Institute of Physico-chemical Biology, Faculty of Bioengineering and Bioinformatics, Moscow 119992, Russia. Electronic address: Sergei.Zaitsev@ki.se.
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Zaitsev
mesh_terms: D001572:Benzofurans / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: C101943:2-(2-imidazolin-2-yl)-1-phenyl-1H-indole; D001572:Benzofurans; D002219:Carbamates; D007004:Hypoglycemic Agents; D007093:Imidazoles; D007211:Indoles; D010880:Piperidines; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; C072379:repaglinide; C062597:efaroxan; D005947:Glucose; D005905:Glyburide; D004121:Dimethyl Sulfoxide
keywords: Endothelial dysfunction; Glibenclamide; Glucose toxicity; Imidazoline; Repaglinide; VEGF