REGULATION OF HUMAN GLUCOSE HOMEOSTASIS BY THE NOVEL CHC22 CLATHRIN ISOFORM

点击翻译按钮获取中文摘要

Type 2 Diabetes (T2D) and Insulin Resistance (IR), which result in excessively high blood sugar (glucose), generate major health problems affecting 382 million people worldwide and ~6% of the UK population, creating an enormous economic burden on modern society. Development of effective therapies is imperative, and requires fundamental research to identify new therapeutic targets and improve our understanding of human glucose metabolism. This research grant focuses on CHC22 clathrin, a novel regulator of human glucose transport, with potential to influence the health and wellbeing of people living with T2D and IR.Proteins are molecular machines inside cells, and like any machine, a protein must be at the right place at the right time to perform its function properly. Clathrins are proteins responsible for transporting other proteins from one part of the cell to another, a process known as intracellular trafficking. The proposed research investigates a form of clathrin called CHC22 that we have found plays a role in intracellular trafficking of the GLUT4 glucose transporter protein, which regulates blood glucose levels.After a meal, insulin is secreted from the pancreas. In response, glucose is imported from the blood into muscle and fat by GLUT4, a channel through which glucose can pass. During fasting, GLUT4 is held inside cells in the GLUT4 storage compartment (GSC). GLUT4 is released from the GSC to the cell surface in response to insulin produced after feeding, allowing glucose uptake and clearance from blood. In IR, tissues stop releasing GLUT4 and importing glucose in response to insulin, and eventually the pancreas stops secreting insulin (T2D). We have observed that, in muscle from T2D patients, when GLUT4 does not get to the surface after insulin stimulation, GLUT4 is trapped in the GSC together with excessive amounts of our protein of interest, CHC22 clathrin. We hypothesize that the presence of CHC22 at the non-functional GSC contributes to IR.The most familiar role of clathrin is to move proteins from the cell surface to the inside of the cell, known as endocytosis. Multiple molecules of clathrin assemble to form a coat on the inside surface of the cell. The coat pulls the membrane to the inside and eventually the membrane breaks away, forming a coated structure that takes cell-surface proteins with it and carries this cargo to specific intracellular locations. In humans, there are two types of clathrin. Unlike the common CHC17 form, CHC22 is not involved in endocytosis, but has a specialized role in transporting GLUT4 to the GSC. We will characterize this role by analyzing the molecular and cellular properties of CHC22 and how its function is controlled by other proteins. Proposed experiments will define how and where formation of the CHC22 clathrin coat is regulated in cells and characterise CHC22 behaviour changes in response to insulin and and IR. We will also explore the differences between two forms of CHC22 proteins found in humans - differences that may influence the development of IR. Together, these studies will reveal the molecular control of CHC22 function in human glucose regulation.Scientists studying GLUT4 have not yet fully defined properties and regulation of the human GSC, and our experiments will shed light on this fundamental aspect of human nutrition. We will also develop new tools that can be used by other researchers studying IR and T2D. Our studies will further clarify the field of clathrin biology, which has been primarily focused on the roles of CHC17.