DOC2B enhanced muscle insulin sensitivity by interacting with cytoskeletal proteins

Abstract

Strategy to enhance skeletal muscle insulin sensitivity is a primary way to substantially reduce the risk of diabetes. Evidences have shown that whole‐body DOC2B over‐expressing mice have enhanced peripheral insulin sensitivity. However, the level of contribution of skeletal muscle specific DOC2B accounting for this enhancement and the underlying mechanism remain unclear. Towards this, we generated a new tetracycline/doxycycline (DOX)‐inducible skeletal muscle specific DOC2B over‐expressing mouse model and demonstrated that the DOC2B enrichment in skeletal muscle is sufficient to enhance peripheral insulin sensitivity as well as whole‐body glucose tolerance. Inaddition, DOC2B overexpressing mice exhibited an increase in insulin‐stimulated GLUT4 accumulation at the plasma membrane and this effect of DOC2B overexpression on promoting insulin stimulated GLUT4 translocation was further confirmed in L6 skeletal muscle cells. Importantly, DOC2B overexpression was sufficient to restore GLUT4 translocation in cells rendered insulin resistant. Proteomic analyses and co‐immunoprecipitation indicate that DOC2B interacts with cytoskeletal proteins. We also found that insulin stimulation phosphorylates DOC2B, which enhances the binding of DOC2B to cytoskeletal proteins to promote GLUT4 translocation and glucose uptake. These results support DOC2B as a potential drug target to restore insulin sensitivity in pre‐diabetic and type 2 diabetic individuals.Support or Funding InformationThis work was supported by grants from the NIH/NIDDK (R01 DK067912; R01 DK102233, to Dr. Debbie Thurmond and the American Heart Association (17POST33661194) to Dr. Jing Zhang. Additional financial support was provided to Dr. Debbie Thurmond.: the Ruth and Robert Lanman Endowment, the George Schaeffer award, and an Excellence award, through the City of Hope.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.