Elucidation of Final Stages in Coupling of Insulin Signalling to CLUT4 Translocation

Maintenance of blood glucose levels is critically dependent on insulin stimulated glucose transport in adipose tissue, heart and skeletal muscle. Insulin combines with its receptor on target tissues and this initiates a cascade of linked reactions that ultimately result in the fusion of vesicles containing the glucose transporter protein GLUT4 with the plasma membrane. This latter process increases the availability of transporter molecules and thereby increases glucose transport into the cell. Although many of the links in the cascade are well studied, many technical difficulties have prevented detailed study of the final steps in the sequence, namely the fusion process. The proposed project will utilise novel approaches to study the fusion reaction and the extent to which small G-proteins of the Rab family link with the fusion machinery. We have identified many similarities between the membrane fusion reactions that occur in the pancreatic beta cell (which lead to secretion of insulin) and in insulin target tissues (which are involved in GLUT4 vesicle fusion). These similarities will guide the research objectives and experimental plans. These plans will be directed at advancing knowledge of how specific and known components of the fusion mechanism are linked together by effector proteins that are downstream of Rab proteins. This work is important as the fundamental mechanism that links signalling to regulated membrane fusion underlies many processes in biology and is relevant to human health. Elucidation of common mechanisms for pancreatic insulin-vesicle traffic and insulin target cell GLUT4-vesicle traffic will allow a unification of our understanding of those key reactions that are critical for control of blood glucose. These may become dysfunctional by a common route in metabolic disease including obesity and type 2 diabetes.