title: Comparison of effects of pioglitazone and glimepiride on plasma soluble RAGE and RAGE expression in peripheral mononuclear cells in type 2 diabetes: randomized controlled trial (PioRAGE).
abstract: OBJECTIVE
  The receptor for advanced glycation end-products (RAGE) is involved in vascular complications in diabetic patients. Pioglitazone, in contrast to glimepiride, has been shown to be protective against atherosclerotic disorders. In this study, we directly compared the effects of those drugs on RAGE system.
  
  
  METHODS
  Sixty-three type 2 diabetic patients (age 20-80 years, hemoglobin A1c 6.4-10.3%) being treated with sulfonylurea (glimepiride 0.5-2.0 mg/day, glyclazide 20-80 mg/day, glibenclamide 1.25-5.0 mg/day), or with nateglinide or metiglynide were randomly assigned to receive either pioglitazone (n = 31) or glimepiride (n = 32). Levels in plasma of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE), and RAGE expression in peripheral mononuclear cells were determined at 0, 12, and 24 weeks.
  
  
  RESULTS
  Twenty-seven patients in the pioglitazone group (15-30 mg) and 30 in the glimepiride group (0.5-4 mg) completed the 24-week trial. Increases in plasma esRAGE were significantly greater in the pioglitazone group (12 weeks: 55 ± 15 pg/mL, p = 0.018; 24 weeks: 90 ± 14 pg/mL, p = 0.003) as compared to the glimepiride group (12 weeks: 12 ± 9 pg/mL; 24 weeks: 29 ± 14 pg/mL). Increases in plasma sRAGE were also significantly (p = 0.037) higher in the pioglitazone group at 24 weeks (170 ± 166 vs.74 ± 171 pg/mL). Furthermore, RAGE expression in mononuclear cells was significantly (p = 0.008) decreased to a greater degree in the pioglitazone group at 24 weeks (-7.39 ± 5.18 vs. -3.39 ± 5.72 MFI). Changes in HbA1c, IRI, and insulin resistance index (HOMA) at 24 weeks were not significantly different between the groups.
  
  
  CONCLUSIONS
  Pioglitazone suppresses RAGE expression and increases circulating sRAGE/esRAGE, and those activities are not necessarily dependent on plasma glucose or insulin resistance levels.
  
  
  BACKGROUND
  UMIN000002055.
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan. Electronic address: hkoyama@hyo-med.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Koyama
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Monden
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Takuhito
authors.initials: T
authors.lastname: Shoji
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Morioka
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukumoto
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Mori
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Emoto
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Shoji
authors.affiliation: Department of Stochastics, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Fukui
authors.affiliation: Center for Drug & Food Clinical Evaluation, Osaka City University Hospital, Osaka 540-0051, Japan.
authors.forename: Hisako
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nishizawa
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inaba
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007333:Insulin Resistance; D007564:Japan; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000077205:Pioglitazone; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000077205:Pioglitazone; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C517652:hemoglobin A1c protein, human; C057619:glimepiride
keywords: Randomized clinical trial; Receptor for advanced glycation end-products (RAGE); Soluble RAGE; Thiazolidinedione