Role of Rab3 in peripheral tissue insulin resistance

糖尿病是一种慢性代谢疾病，全世界有4.15亿人患有糖尿病，英国有330万人患有糖尿病。90%的糖尿病患者患有2型糖尿病。2型糖尿病的特点是肌肉和脂肪组织无法对胰岛素的生理水平做出反应（外周组织胰岛素抵抗），也无法恢复血液中的正常糖水平。外周组织胰岛素抵抗和2型糖尿病的发展与生活方式和肥胖密切相关，尽管潜在的机制尚未完全解决。在健康个体中，当胰岛素与其靶组织（肌肉和脂肪组织）上的受体结合时，会引发一系列连锁反应，最终导致含有葡萄糖转运蛋白（称为GLUT4）的膜泡与细胞表面膜融合。后一过程增加葡萄糖转运分子的可用性，从而增加葡萄糖转运到细胞内。当脂肪细胞处于压力之下时，例如当它们需要在超重的人体内储存大量营养物质时，它们会分泌一种叫做细胞因子的小分子，这种小分子会引发周围组织的炎症反应。这种细胞因子就是TNFa。脂肪细胞分泌TNFa与超重受试者的低度慢性炎症的发展和胰岛素抵抗的发展有关。TNFa对脂肪细胞本身也有直接影响。它在细胞内诱发一系列事件，改变细胞对胰岛素的反应能力，增加细胞表面葡萄糖转运体GLUT4的数量。在我们最近发表的研究中，我们报告了我们的发现，一种名为Rab3的小蛋白对GLUT4靶向到细胞表面膜很重要。最近，我们还发现，在脂肪细胞中，TNFa处理诱导细胞中Rab3蛋白的数量显著减少。因此，在目前的提案中，我们的目的是研究Rab3在外周组织胰岛素抵抗的发展中所起的作用。为了实现这一目标，我们将使用脂肪细胞的细胞模型来研究Rab3和细胞中其他蛋白质之间的分子相互作用，这些蛋白质作为胰岛素在其受体和GLUT4转运蛋白之间的分子联系。我们将研究这些相互作用如何受到tnf或其他已知诱导胰岛素抵抗状态的分子的影响。我们将利用我们实验室最近开发的独特工具来监测Rab3的活性和GLUT4向细胞表面的运动。这些实验将使我们了解Rab3在胰岛素抵抗状态发展的背景下的作用机制。我们还将在人类中进行研究，通过饮食和运动干预计划，Rab3是否以某种方式受到影响，从而揭示脂肪组织和骨骼肌中胰岛素敏感性调节控制的潜在机制。该项目的结果将对我们理解外周组织胰岛素抵抗的发展机制以及开发新的靶向治疗胰岛素抵抗受试者和2型糖尿病患者的疗法具有重要意义。

Diabetes is a chronic metabolic disease affecting 415 million people worldwide and 3.3 million people in the UK. Ninety percent of the people suffering from diabetes have type 2 diabetes. Type 2 diabetes is characterised by the inability of muscle and fat tissues to respond to physiological levels of insulin (peripheral tissue insulin resistance), and to restore the normal levels of sugars in the bloodstream. The development of peripheral tissue insulin resistance and type 2 diabetes is strongly linked to lifestyle and to obesity, although the underlying mechanisms are incompletely resolved. In healthy individual when insulin combines with its receptor on target tissues (muscle and fat tissues) this initiates a cascade of linked reactions that ultimately result in the fusion of membrane vesicles containing the glucose transporter protein (called GLUT4) with the surface membrane of cells. This latter process increases the availability of glucose transporter molecules and thereby increases glucose transport into the cell.When fat cells are under stress, as for example when they need to store large quantities of nutrients in overweight people, they secrete small molecules, called cytokines, which can trigger inflammatory responses in the surrounding tissues. Such a cytokine is TNFa. Secretion of TNFa from fat cells has been linked to the development of a low-grade chronic inflammation in overweight subjects and to the development of insulin resistance. TNFa also has a direct effect on the fat cells themselves. It induces a cascade of events within cells, which alters the ability of the cells to respond to insulin and to increase the numbers of glucose transporters GLUT4 at the cell surface. In our recently published study, we reported our discovery that a small protein called Rab3 is important for the targeting of GLUT4 to the surface membrane of cells. More recently, we also discovered that in adipose cells TNFa treatment induces a very marked decrease in the number of Rab3 proteins in the cells. Therefore, in the current proposal, we aim to investigate the role played by Rab3 in the development of peripheral tissue insulin resistance. To achieve this aim we will use cellular models of adipose cells to investigate the molecular interactions between Rab3 and other proteins in the cell that act as molecular links between insulin action at its receptor and the GLUT4 transporter. We will investigate how these interactions are affected by treatment with TNFa or other molecules known to induce the state of insulin resistance. We will make use of unique tools that were recently developed in our laboratory to monitor the activity of Rab3 and the movement of GLUT4 to the cell surface. These experiments will allow us to understand the mechanisms of action of Rab3 in the context of the development of the insulin-resistant state. We will also investigate in humans, undergoing a diet and exercise intervention programme, whether Rab3 is affected in a manner that reveals underlying mechanisms involved in the control of modulating the insulin sensitivity in adipose tissues and skeletal muscles. The outcome from this project will have important implications for our understanding of the mechanisms of the development of peripheral tissue insulin resistance and for the development of new, targeted therapies for treatment of insulin resistant subjects and people with type 2 diabetes.