Soluble EGFR, a hepatokine, and adipsin, an adipokine, are biomarkers correlated with distinct aspects of insulin resistance in type 2 diabetes subjects

Abstract

Background Insulin resistance can occur in all metabolic organs including the liver, adipose tissue, and skeletal muscles. Circulating soluble epidermal growth factor receptor (soluble EGFR) and adipsin levels are altered in obese diabetic mice and are possibly correlated with insulin resistance in both mice and humans. Here, we investigated the significance of soluble EGFR and adipsin as biomarkers for insulin resistance in Japanese subjects with type 2 diabetes. Methods We measured the soluble EGFR and adipsin levels in sera from 47 non-diabetic subjects and 106 subjects with type 2 diabetes using enzyme-linked immunosorbent assays (ELISAs) and analyzed the correlations between the soluble EGFR or adipsin levels and metabolic parameters in type 2 diabetes subjects. We also measured the gene expression levels of Egfr and Cfd (adipsin) in the liver, adipose tissue, and skeletal muscle in mice with/without obesity or diabetes. Results The soluble EGFR levels were correlated with the fasting blood glucose level (P = 0.010), HOMA-IR (P = 0.035), HbA1c level (P = 0.007), HDL-cholesterol level (P = 0.044), and FIB-4 index (P = 0.017) after adjustments for age, sex, and total cholesterol levels. These factors are known to be related to hepatic insulin resistance. The serum adipsin levels were correlated with BMI (P < 0.001), waist circumference (P < 0.001), fasting serum insulin level (P = 0.001), HOMA-IR (P = 0.009), CPR-index (P = 0.045), and FIB-4 index (P = 0.007) after adjustments for age, sex and eGFR levels. Abdominal adiposity leads to the potentiation of these factors. The expression of Egfr was abundant in the liver, while Cfd was predominantly expressed in adipose tissue in mice. Conclusions Soluble EGFR, a hepatokine, is correlated with insulin resistance in the liver, while adipsin, an adipokine, is associated with adipose insulin resistance. Trial registration: UMIN Clinical Trials Registry (www.umin.ac.jp), UMIN000020474. Registered 8 January 2016.

Bioinformatic Reconstruction and Analysis of Gene Networks Related to Glucose Variability in Diabetes and Its Complications

“…Recently it was demonstrated that EGF signal is involved in diabetes-induced vascular dysfunction, remodeling, and transcriptome dysregulation associated with renal involvement [ 89 ]. In patients with type 2 diabetes, soluble EGFR correlates with fasting blood glucose, insulin resistance, and glycated hemoglobin HbA1c [ 90 ]. Interestingly, EGFR can regulate the transcription of proopiomelanocortin [ 91 ], a hypothalamic appetite regulator and ACTH precursor modulated by glucose level [ 92 ].…”

Apolipoprotein C3 and circulating mediators of preadipocyte proliferation in states of lipodystrophy

“…Increased levels of complement proteins have been previously observed in obesity, insulin resistance, and type 2 diabetes mellitus [ [9] , [36] , [37] , [45] ]. Similarly, increased level of circulating soluble EGFR have been shown to positively correlate with hepatic insulin resistance in both obese mice and people with type 2 diabetes [ 21 ]. The abundance of these proteins also correlated with the insulin resistance present in the Ai-DKO mice at Day 30 [ 41 ], suggesting a positive correlation between the levels of these proteins and the impairment in whole-body metabolism.…”

Therapeutic Role of Curcumin in Diabetes: An Analysis Based on Bioinformatic Findings

“…Another previous study indicated that EGFR has a critical role in progressing STZ-induced diabetes in rat models. In a recent clinical study in a Japanese population with type 2 diabetes, soluble EGFR as a hepatokine was indicated to be associated with insulin resistance in the liver [ 60 ]. In clinical research in 2020, over 7.6 years of monitoring and follow-up reported that the change of the annual mean EGFR in type 1 diabetes was −5.7 and in healthy people, it was 0.6 mL/min/1.73 m 2 , which demonstrates the potential rapid biomarker and possible therapeutic targets for individuals with type 2 diabetes [ 61 ].…”