1549-P: scEMC10 Promotes Glucose Intolerance via the Inhibition of PKA-Mediated Insulin Secretion Free

It has been shown recently that overexpression of the secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) impairs, whereas Emc10 knockout (KO) or antibody neutralization of circulating scEMC10 improves glucose tolerance in mice fed with high fat diet. In humans, serum scEMC10 levels correlate positively with fasting plasma glucose and HbA1c. The mechanism underlying the regulation of glucose metabolism by scEMC10 remains largely unknown. In this study, alation of EMC10 significantly improved glucose tolerance in chow diet-fed mice, which was attributed to increased glucose-stimulated insulin secretion (GSIS), but not improved insulin sensitivity evaluated by euglycemic-hyperinsulinemic clamp. Using an adeno-associated virus, either reconstitution of scEMC10 in Emc10 KO mice or overexpression of scEMC10 in wildtype mice significantly decreased glucose tolerance accompanied by blunted GSIS. Recombinant scEMC10 inhibited GSIS in both INS-1 cells and isolated primary islets in vitro. Mechanistically, we presented evidence that extracellular scEMC10 can be transported into beta cells where it binds to the catalytic subunit of PKA and inhibits phosphorylations of PKA substrates including phosphorylated CREB, along with reduced PDX-1 expression. Furthermore, antibody neutralization of circulating scEMC10 alleviated hyperglycemia in both STZ-treated mice and ob/ob mice. This work identifies scEMC10 as a suppressor of insulin secretion via the inhibition of PKA signaling in islet beta cells and suggests scEMC10 neutralizing antibody as a promising pharmaceutical agent to treat diabetes.