Serum levels of advanced glycation end products (AGEs) are independently correlated with circulating levels of dipeptidyl peptidase-4 (DPP-4) in humans

ObjectivesInhibition 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.Design and methodsThe 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.ResultsMean 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 (R2 = 0.167). Western blot analysis revealed that AGEs significantly increased DPP-4 expression in, and soluble DPP-4 release from tubular cells.ConclusionsThe 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.

► Serum levels of AGEs were independently correlated with circulating DPP-4.
► AGEs increased DPP-4 expression in tubular cells.
► AGEs stimulated the release of DPP-4 from tubular cells.
► AGEs may regulate circulating DPP-4 levels in humans.