Formation and regulation of the human insulin-responsive intracellular GLUT4 transport pathway

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Type 2 diabetes (T2D) affects the health of approximately 400 million people worldwide and generates a huge financial burden for the NHS. Thus, the development of new treatments for diabetes is vital to both individuals and society. To identify new therapeutic targets, we must better understand the pathways that malfunction in T2D. A key characteristic of T2D is a failure of the sugar transporter, GLUT4, to respond to insulin. In healthy muscle and fat cells, GLUT4 stays inside the cell when blood sugar levels are low. After eating, blood sugar levels rise, leading to the release of insulin into the bloodstream, which in turn stimulates GLUT4 to move to the surface of the cell. At the cell surface, GLUT4 transports sugar from the blood into muscle and fat, thereby lowering blood sugar and preventing it from becoming too high after a meal (called hyperglycaemia). However, in insulin-resistant diabetic patients, GLUT4 does not move to the cell surface in response to insulin, and consequently blood sugar levels can elevate dramatically after eating. Long-term high blood sugar is damaging to blood vessels, which carry important nutrients to all tissues in the body, so many organs start to function poorly. It is therefore critical to understand how muscle and fat cells control the movement (termed 'trafficking') of GLUT4 to allow it to be insulin-responsive, and how this malfunctions in people who are insulin-resistant. Clathrin is a protein that is essential for this trafficking process inside cells. Clathrin forms coats that surround cargo, and moves the cargo from one part of the cell to another. We have previously shown that a form of clathrin, called CHC22, traffics GLUT4 as a cargo to a region of the cell called the GLUT4 storage compartment (GSC). GLUT4 is then able to move from the GSC to the cell surface in response to insulin in healthy cells, but gets trapped in the GSC in T2D. Here, we will build on our previous research to determine how the process by which CHC22 traffics GLUT4 to the GSC is regulated, and how this changes in insulin resistance. We will examine the molecular mechanisms that control the action of CHC22, investigating how clathrin coats are both formed and disassembled to identify whether these processes may be therapeutically targeted during insulin resistance in order to increase GLUT4 levels at the cell surface. We will use state-of-the-art imaging techniques to understand what the GSC looks like, imaging this compartment at never-before-possible molecular detail, to see how the GSC changes upon insulin resistance, with the goal of identifying features of the GSC that could be targeted to increase release of GLUT4 from this compartment to the cell surface in cases of insulin resistance.Together, these experiments will define the role and mechanism of CHC22 in GLUT4 trafficking, with the long-term goal of identifying potential new drug targets that act on CHC22 to change how GLUT4 is trafficked in insulin-resistant patients, in order to improve their ability to control blood sugar levels.