Kyohara Mayu, Shirakawa Jun, Okuyama Tomoko, Kimura Ayuko, Togashi Yu, Tajima Kazuki, Hirano Hisashi, Terauchi Yasuo
Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Japan.
Advanced Medical Research Center, Yokohama City University, Japan.
Endocrinology. 2017 Dec 1;158(12):4152-4164. doi: 10.1210/en.2017-00339.
To identify circulating factors as candidates involved in type 2 diabetes mellitus (T2DM), we conducted two different quantitative proteomic analyses: (1) db/db mouse sera were compared with db/+ mouse sera obtained at 4, 8, 12, and 24 weeks of age, and (2) db/db mouse sera from animals treated with liraglutide were compared with sera from animals without liraglutide treatment. Twenty proteins were differentially expressed in db/db mouse sera in the first experiment and eight proteins were differentially expressed in db/db mouse sera after liraglutide treatment in the second experiment. Soluble epidermal growth factor receptor (sEGFR) was identified as a common factor, and its protein level was significantly affected in both experiments. An enzyme-linked immunosorbent assay confirmed that the relatively low serum sEGFR levels in db/db mice were restored by liraglutide treatment. The serum sEGFR levels were elevated in diabetic mice with impaired insulin secretion and decreased in high-fat diet-fed mice and ob/ob mice. The serum sEGFR levels increased after the administration of a dual inhibitor of IGF-1/insulin receptor or streptozotocin. In humans with normal glucose tolerance or T2DM, the serum sEGFR levels were correlated with the fasting blood glucose, fasting serum insulin, homeostatic model assessment of insulin resistance, HbA1c, total cholesterol, low-density lipoprotein cholesterol, and triglycerides levels. These findings suggest that sEGFR might be a biomarker for evaluating insulin resistance or a therapeutic target of liraglutide.
为了鉴定参与2型糖尿病（T2DM）的循环因子候选物，我们进行了两种不同的定量蛋白质组分析：（1）将db/db小鼠血清与4、8、12和24周龄的db/+小鼠血清进行比较，（2）将接受利拉鲁肽治疗的db/db小鼠血清与未接受利拉鲁肽治疗的小鼠血清进行比较。在第一个实验中，有20种蛋白质在db/db小鼠血清中差异表达，在第二个实验中，有8种蛋白质在利拉鲁肽治疗后的db/db小鼠血清中差异表达。可溶性表皮生长因子受体（sEGFR）被鉴定为一个共同因子，其蛋白水平在两个实验中均受到显著影响。酶联免疫吸附测定证实，利拉鲁肽治疗可恢复db/db小鼠相对较低的血清sEGFR水平。胰岛素分泌受损的糖尿病小鼠血清sEGFR水平升高，高脂饮食喂养的小鼠和ob/ob小鼠血清sEGFR水平降低。给予IGF-1/胰岛素受体双重抑制剂或链脲佐菌素后，血清sEGFR水平升高。在糖耐量正常或患有T2DM的人类中，血清sEGFR水平与空腹血糖、空腹血清胰岛素、胰岛素抵抗稳态模型评估、糖化血红蛋白、总胆固醇、低密度脂蛋白胆固醇和甘油三酯水平相关。这些发现表明，sEGFR可能是评估胰岛素抵抗的生物标志物或利拉鲁肽的治疗靶点。
