The Exocyst Complex is Essential for Insulin Stimulated Glucose Uptake in Skeletal Muscle and Whole-Body Glucose Homeostasis

Abstract

The earliest detectable sign of Type 2 Diabetes Mellitus is reduced insulin stimulated glucose uptake in skeletal muscle. Skeletal muscle is responsible for 80-90% of insulin stimulated glucose uptake. In the basal state, the membrane bound GLUT4 is sequestered in regions of the cytosol as GLUT4 storage vesicles. When stimulated by insulin, GLUT4 is incorporated into plasma membrane by the process of exocytosis. Conserved from yeast to humans, the Exocyst complex is important for the targeted delivery and docking of cytoplasmic vesicles to the plasma membrane. It has been demonstrated that the Exocyst complex is essential for insulin stimulated GLUT4 exocytosis in adipocytes. Our studies have demonstrated that the Exocyst complex is also critical for GLUT4 exocytosis and glucose uptake in L6-GLUT4myc myoblasts. The Exocyst inhibitor endosidin-2 and a heterozygous knockout of EXOC5 in skeletal myoblast cells both lead to impaired GLUT4 trafficking to the plasma membrane and also hindered glucose uptake. A tamoxifen-inducible skeletal muscle-specific knockout mouse strain of EXOC5 (EXOC5-SMKO) to assess the role of the Exocyst in glucose homeostasis in vivo was generated. EXOC5-SMKO mice had elevated overnight fasting glucose levels and increase body weight after a high fat diet challenge. Male EXOC5-SMKO mice had impaired glucose tolerance, enlarged Islets of Langerhans, and lower serum insulin. The research presented here confirms the central role of the Exocyst complex during insulin stimulated glucose uptake in muscle. This work will help to expand the range of potential targets for therapeutic interventions of Type2 Diabetes Mellitus.