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

人胰岛素反应性细胞内 GLUT4 转运途径的形成和调节

• 批准号: MR/X018377/1
• 负责人: Frances Martha Brodsky
• 金额: $ 83.27万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX018377%2F1
• 关键词: Formation; regulation; human; insulin; responsive

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.

2型糖尿病（T2D）影响全球约4亿人的健康，并为NHS带来巨大的财政负担。因此，开发糖尿病的新疗法对个人和社会都至关重要。为了确定新的治疗靶点，我们必须更好地了解T2D中发生故障的途径。T2D的一个关键特征是糖转运蛋白GLUT 4对胰岛素应答失败。在健康的肌肉和脂肪细胞中，当血糖水平低时，GLUT 4会留在细胞内。进食后，血糖水平上升，导致胰岛素释放到血液中，这反过来又刺激GLUT4移动到细胞表面。在细胞表面，GLUT 4将血糖从血液中转运到肌肉和脂肪中，从而降低血糖并防止其在餐后变得过高（称为高血糖症）。然而，在胰岛素抵抗的糖尿病患者中，GLUT4不会响应胰岛素而移动到细胞表面，因此血糖水平在进食后会急剧升高。长期的高血糖会损害血管，血管将重要的营养物质输送到身体的所有组织，因此许多器官开始功能低下。因此，了解肌肉和脂肪细胞如何控制GLUT 4的运动（称为“贩运”）以使其对胰岛素敏感，以及这种功能如何在胰岛素抵抗的人中发生故障至关重要。网格蛋白是细胞内这种运输过程所必需的蛋白质。网格蛋白形成包裹货物的外壳，并将货物从细胞的一个部分移动到另一个部分。我们之前已经表明，一种称为CHC22的网格蛋白将GLUT 4作为货物运输到称为GLUT 4储存室（GSC）的细胞区域。然后，GLUT4能够响应健康细胞中的胰岛素从GSC移动到细胞表面，但在T2D中被困在GSC中。在这里，我们将建立在我们以前的研究，以确定CHC22交通GLUT 4到GSC的过程是如何调节的，以及如何改变胰岛素抵抗。我们将研究控制CHC22作用的分子机制，研究网格蛋白涂层是如何形成和分解的，以确定这些过程是否可以在胰岛素抵抗期间进行治疗靶向，以增加细胞表面的GLUT 4水平。我们将使用最先进的成像技术来了解GSC的样子，以前所未有的分子细节对该隔室进行成像，以了解GSC在胰岛素抵抗时如何变化，目的是识别GSC的特征，这些特征可以在胰岛素抵抗的情况下靶向增加GLUT 4从该隔室释放到细胞表面。这些实验将确定CHC22在GLUT4运输中的作用和机制，长期目标是确定作用于CHC22的潜在新药靶点，以改变胰岛素抵抗患者中GLUT4的运输方式，从而提高他们控制血糖水平的能力。