Role of Rab3 in peripheral tissue insulin resistance

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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.