Type 2 diabetes is the most prevalent form of diabetes in the United States. The major contributing factor to the development of type 2 diabetes is insulin resistance of peripheral tissues, primarily skeletal muscle and adipose tissue. Insulin-mediated translocation and fusion of insulin-responsive glucose transporter (GLUT4)-containing vesicles to the plasma membrane is critical for proper glucose homeostasis. Thus, the identification and characterization of cellular factors and processes regulating GLUT4 trafficking are critical to understanding the molecular mechanisms underlying impaired insulin sensitivity. Insulin signaling coordinates the tethering, docking and fusion of GLUT4 vesicles in part by regulating the actin cytoskeletal. While actin reorganization is required for GLUT4 vesicle trafficking, little is known about the factors regulating the cytoskeletal rearrangements required for these processes. The broad aim of this proposal is to gain insight on the mechanisms regulating the dynamic reorganization of the cytoskeleton during insulin-stimulated GLUT4 vesicle trafficking. The myosin family of actin- based motor proteins, specifically myosin II (MyoII) has been shown to regulate actin filament reorganization to facilitate vesicle traffickig in various cell types. Myosin II has been shown to function in a structural role to aid in the reorganization of the actin cytoskeleton as well as in a motor role to contract actin filaments. Our studies show that the MyoIIA isoform is activated and colocalizes with GLUT4 and filamentous actin (F-actin) at the plasma membrane upon insulin stimulation to facilitate GLUT4-mediated glucose uptake. Furthermore, we show that inhibition of MyoII activity impairs the proper insertion of GLUT4 at the plasma membrane. Since actin is an integral component tethering GLUT4 vesicles at the plasma membrane as well as vesicle fusion events, we hypothesize that MyoIIA facilitates the actin reorganization required for GLUT4 vesicle tethering and fusion with the plasma membrane. Thus, the specific aims of this proposal are to identify and characterize the mechanisms by which MyoIIA regulates the actin cytoskeleton during insulin-stimulated GLUT4 vesicle trafficking in adipocytes.
Type 2 diabetes is a major public health issue affecting approximately 8% of the population in the United States. The prevalence of type 2 diabetes is even higher among African Americans, Hispanics, Native Americans and the elderly. A particularly alarming trend is the rise in the incidence of type 2 diabetes in children. With the increasing incidence of type 2 diabetes it is critical to identify factors contributing to the development of this disease in order to design effective treatments. The proposed research will provide critical information for understanding the molecular mechanism(s) involved in the development of in type 2 diabetes.
