title: Metformin affects macrophages' phenotype and improves the activity of glutathione peroxidase, superoxide dismutase, catalase and decreases malondialdehyde concentration in a partially AMPK-independent manner in LPS-stimulated human monocytes/macrophages.
abstract: BACKGROUND
  Diabetic patients experience accelerated atherosclerosis. Metformin is a cornerstone of the current therapy of type 2 diabetes. Macrophages are the key cells associated with the development of atherosclerotic plaques. Therefore, our aim was to assess the in vitro effects of metformin on macrophages and its influence on the mechanisms involved in the development of atherosclerosis.
  
  
  METHODS
  Peripheral blood mononuclear cells were obtained from the group including 16 age-matched healthy non-smoking volunteers aged 18-40 years. Monocytes were further incubated with metformin, LPS and compound C--a pharmacological inhibitor of AMPK. The impact of metformin on oxidative stress markers, antioxidative properties, inflammatory cytokines and phenotypical markers of macrophages was studied.
  
  
  RESULTS
  We showed that macrophages treated with metformin expressed less reactive oxygen species (ROS), which resulted from increased antioxidative potential. Furthermore, a reduction in inflammatory cytokines was observed. We also observed a phenotypic shift toward the alternative activation of macrophages that was induced by metformin. All the aforementioned results resulted from AMPK activation, but a residual activity of metformin after AMPK blockade was still noticeable even after inhibition of AMPK by compound C.
  
  
  CONCLUSIONS
  Authors believe that metformin-based therapy, a cornerstone in diabetes therapy, not only improves the prognosis of diabetics by reducing blood glucose but also by reducing oxidative stress, inflammatory cytokine production and the shift toward alternative activation of macrophages.
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland. Electronic address: lbuldak@gmail.com.
authors.forename: Łukasz
authors.initials: Ł
authors.lastname: Bułdak
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Łabuzek
authors.affiliation: Department of Physiology, Medical University of Silesia, Zabrze, Poland. Electronic address: fizjozab@slam.katowice.pl.
authors.forename: Rafał Jakub
authors.initials: RJ
authors.lastname: Bułdak
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Kozłowski
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Machnik
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Liber
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Suchy
authors.affiliation: Department of Anesthesiology and Intensive Care, Medical University of Silesia, Katowice, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Duława-Bułdak
authors.affiliation: Department of Internal Medicine and Clinical Pharmacology, Medical University of Silesia, Katowice, Poland.
authors.forename: Bogusław
authors.initials: B
authors.lastname: Okopień
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology; D050197:Atherosclerosis / Q000188:drug therapy / Q000378:metabolism; D002374:Catalase / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D016207:Cytokines; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D008315:Malondialdehyde; D008687:Metformin; D002374:Catalase; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D055372:AMP-Activated Protein Kinases
keywords: Antioxidative enzymes; Macrophages; Metformin; Oxidative stress