Thesis abstract:

«p»Insulin resistance (IR) is a common feature of a suite of pathologies referred to as cardiometabolic diseases, including type 2 diabetes, cardiovascular diseases, and some type of cancers. IR is characterized as a defect in metabolic response to insulin, particularly present in muscle and fat cells, which results in impaired clearance of glucose from the bloodstream. Hence, therapies that improve insulin sensitivity would have enormous utility in preventing many diseases. Impaired trafficking and translocation of the endosomal glucose transporter GLUT4 is recognized as one of the primary defects in IR. However, there is no clarity if this defect is exclusive to GLUT4 trafficking or if IR is a more generalized defect in protein trafficking to the cell surface. The endosomal trafficking system composed of early, late, and recycling endosomes contributes to signal transduction and is essential to metabolic physiology and pathology. Excitingly, our preliminary data showed that the transferrin receptor (TfR, a well-known marker of the endosomal recycling compartment) also trafficked to the cell surface in response to insulin stimulation and was defective in IR, suggesting that IR is likely to be a broader defect in protein trafficking. The main aim of this Ph.D. project is to investigate which proteins are trafficking to the cell surface in response to insulin and which of those are defective in IR. The candidates are explored by using multiple cell models with a systems biology approach and further verified in mouse models. The four objectives are: 1) to identify proteins that traffic to the cell surface in response to insulin in control and IR using advanced proteomics and imaging techniques; 2) to investigate the tissue specificity regarding impaired endosomal trafficking in IR using different cell models; 3) to explore the kinetic changes of endosomal trafficking regulated by insulin and IR; and 4) to validate shortlisted plasma membrane proteins in insulin-resistant mouse models. This project is expected to unravel novel endosomal trafficking mechanisms linking IR and has the potential to vastly expand the repertoire of drug targets for IR-related diseases.«/p»