title: Cyclooxygenase-2 (PTGS2) inhibitors augment the rate of hexose transport in L6 myotubes in an insulin- and AMPKalpha-independent manner.
abstract: OBJECTIVE
  Some cyclooxygenase-2 (COX2, also known as prostaglandin-endoperoxide synthase 2 [PTGS2]) inhibitors have been shown to increase insulin sensitivity in man or induce hypoglycaemic episodes when overconsumed or taken in combination with oral hypoglycaemic drugs. These side-effects and their impact on patients are not always recognised in routine clinical practice. We investigated whether these side-effects of COX2 (PTGS2) inhibitors result from stimulation of the glucose transport system in skeletal muscle cells.
  
  
  METHODS
  L6 myotube cultures were used to study effects of COX2 (PTGS2) inhibitors on the glucose transport system and their relationship to PTGS2 expression, insulin action and AMP-activated protein kinase alpha (AMPKalpha) activity.
  
  
  RESULTS
  The inhibitors niflumic acid, nimesulide and rofecoxib increased the rate of hexose uptake in L6 myotubes in the absence of insulin and in a dose- and time-dependent manner. They did this by increasing the total cell content of member 4 of the solute carrier family 2 (SCLC2A4, previously known as glucose transporter 4 [GLUT4]) (but not SCLC2A1 [previously known as GLUT1]) mRNA and protein and the amount of it in the plasma membrane. AMPKalpha was not involved in the latter effect since the inhibitors did not activate it. In addition, none of the inhibitors modulated the rate of hexose transport in vascular endothelial and smooth muscle cells expressing PTGS2 and SCLC2A1. Prostaglandin-endoperoxide synthase 1 (also known as cyclooxygenase 1) inhibitors (acetylsalicylic acid and indomethacin) did not alter the rate of hexose uptake and SCLC2A4 subcellular distribution in L6 myotubes.
  
  
  CONCLUSIONS
  This study suggests that certain COX2 (PTGS2) inhibitors can alter glucose homeostasis in vivo by stimulating glucose uptake in skeletal muscles that express PTGS2.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Alpert
authors.forename: A
authors.initials: A
authors.lastname: Gruzman
authors.forename: B
authors.initials: B
authors.lastname: Lardi-Studler
authors.forename: G
authors.initials: G
authors.lastname: Cohen
authors.forename: R
authors.initials: R
authors.lastname: Reich
authors.forename: S
authors.initials: S
authors.lastname: Sasson
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006601:Hexoses / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D008297:Male; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009544:Niflumic Acid / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D006601:Hexoses; D007328:Insulin; D007783:Lactones; D009097:Multienzyme Complexes; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D009544:Niflumic Acid; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C012655:nimesulide