Regulation of Intracellular Trafficking in Skeletal Muscle of Type 2 Diabetics

Grant Winners

Dean

Abstract

Type 2 diabetes ranks among the top ten causes of death in most developed nations, and its worldwide incidence is rapidly increasing. Central to type 2 diabetes is loss of sensitivity of cells to insulin. A major consequence is the failure of skeletal muscle cells to move insulin-sensitive glucose transporters (GLUT4) to surface membranes where they lower blood glucose by transporting glucose from the bloodstream into the muscle cells. With insufficient GLUT4 translocation to muscle cell surfaces hyperglycemia and its harmful effects ensue. The normal process of GLUT4 translocation is poorly understood, so in previous experiments gene expression profiling using insulin-treated tissue culture muscle cells was used to identify mRNAs regulated by insulin. Four insulin-regulated mRNAs were found in the gene expression profiling that encode proteins having roles in intracellular trafficking making them candidates to have importance in GLUT4 translocation: ArgBP2, BIN1, caveolin 3, and kinesin-related protein 1 (KRP1). This application is to fund studies to test the hypothesis that these proteins are relevant to the human disease type 2 diabetes. The experimental approach would be assaying protein by western blot isolated from normal and diabetic human skeletal muscle samples obtained postmortem in order to determine which, if any, of the four candidates have protein quantities that are modulated in the disease. This knowledge would enhance our understanding at the molecular level of how cells respond to insulin, and how that response is altered in type 2 diabetes.