title: Statins impair glucose uptake in human cells.
abstract: OBJECTIVE
  Considering the increasing number of clinical observations indicating hyperglycemic effects of statins, this study was designed to measure the influence of statins on the uptake of glucose analogs by human cells derived from liver, adipose tissue, and skeletal muscle.
  
  
  METHODS
  Flow cytometry and scintillation counting were used to measure the uptake of fluorescently labeled or tritiated glucose analogs by differentiated visceral preadipocytes, skeletal muscle cells, skeletal muscle myoblasts, and contact-inhibited human hepatocellular carcinoma cells. A bioinformatics approach was used to predict the structure of human glucose transporter 1 (GLUT1) and to identify the presence of putative cholesterol-binding (cholesterol recognition/interaction amino acid consensus (CRAC)) motifs within this transporter. Mutagenesis of CRAC motifs in SLC2A1 gene and limited proteolysis of membrane GLUT1 were used to determine the molecular effects of statins.
  
  
  RESULTS
  Statins significantly inhibit the uptake of glucose analogs in all cell types. Similar effects are induced by methyl-β-cyclodextrin, which removes membrane cholesterol. Statin effects can be rescued by addition of mevalonic acid, or supplementation with exogenous cholesterol. Limited proteolysis of GLUT1 and mutagenesis of CRAC motifs revealed that statins induce conformational changes in GLUTs.
  
  
  CONCLUSIONS
  Statins impair glucose uptake by cells involved in regulation of glucose homeostasis by inducing cholesterol-dependent conformational changes in GLUTs. This molecular mechanism might explain hyperglycemic effects of statins observed in clinical trials.
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland ; Genomic Medicine, Department of General, Transplant and Liver Surgery , Medical University of Warsaw , Warsaw , Poland.
authors.forename: Dominika
authors.initials: D
authors.lastname: Nowis
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Malenda
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Karolina
authors.initials: K
authors.lastname: Furs
authors.affiliation: Chair of General Biology and Parasitology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Bozenna
authors.initials: B
authors.lastname: Oleszczak
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Sadowski
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Justyna
authors.initials: J
authors.lastname: Chlebowska
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Firczuk
authors.affiliation: Laboratory of Bioinformatics and Protein Engineering , International Institute of Molecular and Cell Biology in Warsaw , Warsaw , Poland ; Bioinformatics Laboratory , Institute of Molecular Biology and Biotechnology, Adam Mickiewicz University , Poznan , Poland.
authors.forename: Janusz M
authors.initials: JM
authors.lastname: Bujnicki
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Staruch
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Radoslaw
authors.initials: R
authors.lastname: Zagozdzon
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Eliza
authors.initials: E
authors.lastname: Glodkowska-Mrowka
authors.affiliation: Chair of General Biology and Parasitology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland.
authors.forename: Leszek
authors.initials: L
authors.lastname: Szablewski
authors.affiliation: Department of Immunology , Center of Biostructure Research, Medical University of Warsaw , Warsaw , Poland ; Institute of Physical Chemistry, Polish Academy of Sciences , Warsaw , Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Golab
keywords: GLUT1; Glucose Uptake; Pharmacological Therapy