Department of Medicine, Division of Cardio-Vascular Medicine, Kurume University School of Medicine, Kurume, Japan.
Clin Biochem. 2013 Mar;46(4-5):300-3. doi: 10.1016/j.clinbiochem.2012.11.023. Epub 2012 Dec 4.
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.
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.
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.
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.
二肽基肽酶-4（DPP-4）的抑制作用被认为是 2 型糖尿病的一种潜在治疗靶点。尽管已经在人血清中鉴定出可溶性 DPP-4，并且它可能与 DPP-4 活性有关，但循环 DPP-4 水平的动力学和调节仍不清楚。在这项研究中，我们研究了哪些人体测量和代谢变量，包括晚期糖基化终产物（AGEs）的血清水平，与血清 DPP-4 水平独立相关。此外，我们还研究了 AGEs 对人肾小管上皮细胞中 DPP-4 表达和可溶性 DPP-4 释放的影响。
这项研究涉及 432 名连续门诊患者（301 名男性和 131 名女性；平均年龄 61.8±8.8 岁），他们接受了完整的病史和体格检查，并进行了血液化学和人体测量变量的测定。通过酶联免疫吸附试验检测血清 DPP-4 和 AGE 水平。用 Western blot 分析检测 DPP-4 的蛋白表达水平及其从细胞中的释放。
血清 DPP-4 和 AGEs 的平均水平分别为 520.2±39.9ng/ml 和 8.96±2.57U/ml。多元回归分析显示，女性（p<0.001）、高密度脂蛋白胆固醇（p<0.001）、糖化血红蛋白（p<0.001）、AGEs（p<0.03）和无高血压药物治疗（p<0.05）与 DPP-4 水平独立相关（R²=0.167）。Western blot 分析显示，AGEs 显著增加了肾小管细胞中 DPP-4 的表达和可溶性 DPP-4 的释放。
本研究表明，血清 DPP-4 水平与一般人群中的各种代谢参数独立相关。AGEs 可能上调细胞内 DPP-4 的表达，进而增加循环 DPP-4 的水平。
