Zinc-finger BED domain-containing 3 (Zbed3) is a novel secreted protein associated with insulin resistance in humans

Genome-wide association studies (GWAS) have shown that Zbed3 is associated with T2DM. To date, no report has demonstrated a relationship between Zbed3 and insulin resistance in humans, however. The purpose of this study was to determine whether the Zbed3 protein is secreted and identify any associations between Zbed3 and insulin resistance in cross-sectional and interventional studies.

We found that Zbed3 protein was secreted in an in vitro secretion study. Plasma Zbed3 levels were determined in an ELISA and were compared with various parameters related to insulin resistance in subjects with NGT, IGT and nT2DM. EHC was performed in healthy subjects. Real-time PCR and Western blotting were used to assess the mRNA and protein expression of Zbed3.

Zbed3 was detected in an analysis of in vitro secretion in both conditioned medium and lysates of HEK-293T cells transfected with an overexpressed vector. In a clinical study, there were significantly higher levels of circulating Zbed3 in IGT and nT2DM relative to NGT. Zbed3 levels were positively correlated with BMI, WHR, FAT%, blood pressure, FBG, TG, HbA1c, FIns and HOMA-IR and inversely correlated with HDL-C. Increasing levels of Zbed3 were independently associated with IGT and T2DM. Zbed3 mRNA and protein in muscle and fat were significantly elevated in both db/db mice and T2DM patients. Moreover, there was a concentration-dependent effect of glucose on Zbed3 release, whereas insulin exhibited an inhibitory effect on Zbed3 levels. Zbed3 suppressed insulin-induced IR and Akt phosphorylation.

These results suggest that the Zbed3 protein may be a cytokine associated with insulin resistance in humans that is influenced by glucose and insulin levels.