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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.

Serum Quantitative Proteomic Analysis Reveals Soluble EGFR To Be a Marker of Insulin Resistance in Male Mice and Humans