Secreted EMC10 inhibits muscle GLUT4 activity and glucose uptake in mice.

Manipulation of glucose uptake plays a critical role in muscle glucose disposal. We have shown that the secreted isoform of endoplasmic reticulum membrane protein complex subunit 10 (scEMC10) impairs glucose tolerance in mice, and serum scEMC10 is positively associated with insulin resistance and hyperglycemia in humans. In this study, we attempt to investigate whether modulation of muscle glucose uptake implicates in the scEMC10-impacted glucose homeostasis. In mouse models, Emc10 gene KO elevated, whereas recombinant scEMC10 treatment reduced muscle glucose uptake and GLUT4 expression. In myoblasts, scEMC10 inhibited both GLUT4 expression and membrane translocation and downregulated expression of genes associated with intracellular glucose metabolism. Mechanistically, scEMC10 suppressed the activation of muscle AMP-activated protein kinase and insulin signaling cascades. Inhibition of scEMC10 via a neutralizing antibody enhanced muscle glucose uptake in mice, in parallel with heightened GLUT4 expression and membrane translocation, which accounts for an improved whole-body glucose homeostasis. In conclusion, this work identifies scEMC10 as a novel suppressor of muscle glucose uptake and suggests inhibition of scEMC10 as a therapeutic strategy for type 2 diabetes.