title: Methotrexate reduces HbA1c concentration but does not produce chronic accumulation of ZMP in patients with rheumatoid or psoriatic arthritis.
abstract: OBJECTIVE
  The mechanism by which methotrexate (MTX) improves glucose homeostasis in patients with rheumatoid (RA) and psoriatic arthritis (PsA) remains undetermined. Animal studies indicate a role for intracellular accumulation of 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosyl 5'-monophosphate (ZMP) but this has not been directly demonstrated in humans. We explored whether accumulation of ZMP is associated with improvements in glucose homeostasis during MTX therapy.
  
  
  METHODS
  MTX-naïve, non-diabetic RA (n = 16) and PsA (n = 10) patients received uninterrupted MTX treatment for 6 months. To evaluate whether ZMP accumulated during MTX therapy, we measured the concentration of ZMP in erythrocytes and the concentration of its dephosphorylated derivative 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR) in urine using liquid chromatography mass spectrometry (LC-MS/MS). To assess glucose homeostasis, we determined the concentration of glycated haemoglobin (HbA1c) and homeostasis model assessment of insulin resistance [HOMA-IR: fasting glucose (mmol/L) × fasting insulin (μU/mL)/22.5].
  
  
  RESULTS
  Erythrocyte ZMP and urinary AICAR concentrations did not increase during 6 months of MTX therapy. HbA1c concentration was reduced from 5.80 ± 0.29% at baseline to 5.51 ± 0.32% at 6 months (p < 0.001), while HOMA-IR remained unaltered. Reduction in HbA1c concentration was not associated with increased ZMP or AICAR concentrations.
  
  
  CONCLUSIONS
  MTX therapy probably does not produce a chronic increase in erythrocyte ZMP or urinary AICAR concentrations. Collectively, our data do not support the hypothesis that MTX improves glucose homeostasis through chronic accumulation of ZMP.
authors.affiliation: a Department of Rheumatology , University Medical Centre Ljubljana , Slovenia.
authors.forename: K
authors.initials: K
authors.lastname: Perdan-Pirkmajer
authors.affiliation: b Institute of Pathophysiology, Faculty of Medicine , University of Ljubljana , Slovenia.
authors.forename: S
authors.initials: S
authors.lastname: Pirkmajer
authors.affiliation: c Institute of Biochemistry, Centre for Preventive Doping Research , German Sport University Cologne , Germany.
authors.forename: M
authors.initials: M
authors.lastname: Thevis
authors.affiliation: c Institute of Biochemistry, Centre for Preventive Doping Research , German Sport University Cologne , Germany.
authors.forename: A
authors.initials: A
authors.lastname: Thomas
authors.affiliation: a Department of Rheumatology , University Medical Centre Ljubljana , Slovenia.
authors.forename: S
authors.initials: S
authors.lastname: Praprotnik
authors.affiliation: a Department of Rheumatology , University Medical Centre Ljubljana , Slovenia.
authors.forename: A
authors.initials: A
authors.lastname: Hočevar
authors.affiliation: a Department of Rheumatology , University Medical Centre Ljubljana , Slovenia.
authors.forename: Ž
authors.initials: Ž
authors.lastname: Rotar
authors.affiliation: a Department of Rheumatology , University Medical Centre Ljubljana , Slovenia.
authors.forename: N
authors.initials: N
authors.lastname: Gašperšič
authors.affiliation: a Department of Rheumatology , University Medical Centre Ljubljana , Slovenia.
authors.forename: S
authors.initials: S
authors.lastname: Sodin-Šemrl
authors.affiliation: d Faculty of Health Sciences , University of Ljubljana , Slovenia.
authors.forename: J
authors.initials: J
authors.lastname: Žibert
authors.affiliation: e Faculty of Pharmacy , University of Ljubljana , Slovenia.
authors.forename: J
authors.initials: J
authors.lastname: Omersel
authors.affiliation: f Department of Molecular Medicine and Surgery, Integrative Physiology , Karolinska Institutet , Stockholm , Sweden.
authors.forename: A V
authors.initials: AV
authors.lastname: Chibalin
authors.affiliation: a Department of Rheumatology , University Medical Centre Ljubljana , Slovenia.
authors.forename: M
authors.initials: M
authors.lastname: Tomšič
authors.affiliation: a Department of Rheumatology , University Medical Centre Ljubljana , Slovenia.
authors.forename: A
authors.initials: A
authors.lastname: Ambrožič
mesh_terms: D000328:Adult; D000368:Aged; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000378:metabolism; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D015535:Arthritis, Psoriatic / Q000188:drug therapy* / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism*; D002853:Chromatography, Liquid; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D011446:Prospective Studies; D012265:Ribonucleotides / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D000620:Aminoimidazole Carboxamide; D018501:Antirheumatic Agents; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007328:Insulin; D008727:Methotrexate; D012265:Ribonucleotides; C517652:hemoglobin A1c protein, human; C031143:AICA ribonucleotide