title: Serum levels of advanced glycation end products (AGEs) are independently correlated with circulating levels of dipeptidyl peptidase-4 (DPP-4) in humans.
abstract: OBJECTIVE
  Inhibition of dipeptidyl peptidase-4 (DPP-4) has been proposed as a potential therapeutic target for type 2 diabetes. Although soluble DPP-4 has been identified in human serum and could be associated with DPP-4 activity, the kinetics and regulation of circulating DPP-4 levels remain unknown. In this study, we examined which anthropometric and metabolic variables, including serum levels of advanced glycation end products (AGEs), were independently associated with serum DPP-4 levels. Further, we investigated the effects of AGEs on DPP-4 expression in, and soluble DPP-4 release from human cultured proximal tubular epithelial cells.
  
  
  METHODS
  The study involved 432 consecutive outpatients (301 males and 131 females; mean ages 61.8 ± 8.8) who underwent complete history and physical examinations, and determinations of blood chemistry and anthropometric variables. Serum DPP-4 and AGE levels were examined by enzyme-linked immunosorbent assay. Protein expression levels of DPP-4 and its release from the cells were analyzed with western blot analysis.
  
  
  RESULTS
  Mean serum levels of DPP-4 and AGEs were 520.2 ± 39.9 ng/mL and 8.96 ± 2.57 U/mL, respectively. In multiple regression analysis, female (p<0.001), HDL-cholesterol (p<0.001), glycated hemoglobin (p<0.001), AGEs (p<0.03), and the absence of hypertension medication (p<0.05) are independently associated with DPP-4 levels (R(2)=0.167). Western blot analysis revealed that AGEs significantly increased DPP-4 expression in, and soluble DPP-4 release from tubular cells.
  
  
  CONCLUSIONS
  The present study reveals that serum levels of DPP-4 are independently associated with various metabolic parameters in a general population. AGEs may up-regulate cellular DPP-4 expression and subsequently increase circulating levels of DPP-4 in humans.
authors.affiliation: Department of Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Kurume, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tahara
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Tahara
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kaifu
authors.forename: Seiji
authors.initials: S
authors.lastname: Ueda
authors.forename: Seiya
authors.initials: S
authors.lastname: Okuda
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D018819:Dipeptidyl Peptidase 4 / Q000097:blood*; D005260:Female; D017127:Glycation End Products, Advanced / Q000097:blood*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D017127:Glycation End Products, Advanced; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4