Skeletal muscle is the primary tissue for uptake and storage of glucose. This is mediated by insulin, which, after binding to the insulin receptor, triggers a complex series of signalling pathways that ultimately lead to the translocation of the insulin-responsive glucose transporter GLUT4 to the cell surface. Any disturbance in these pathways results in insulin resistance, which is characterised by hyperglycaemia and disordered lipid metabolism, ultimately leading to diabetes. Similarly, obesity induces insulin resistance in adipose tissue, liver and muscle. Since obesity is on the rise worldwide, the molecular mechanisms that underlie insulin resistance and diabetes are of great interest in the search for solutions to this serious global health problem.

Integrins constitute the major family of cell surface adhesion receptors, mediating both cell-cell and cell-matrix interactions. Evidence suggests a pivotal role for integrins in insulin signalling, but the molecular pathways that underpin this are not completely understood. We have previously generated a mouse model with a targeted inactivation of integrin α7β1, the predominant integrin in adult skeletal muscle. Preliminary data from our laboratory indicate that insulin signalling is altered in α7β1-deficient mice, but the underlying mechanisms have not been elucidated. This project will use transgenic mice to define the phenotypes observed and gain insights into the potentially crucial role integrins play in regulating insulin signalling.  By undertaking this project, you will gain expertise in a variety of core scientific techniques, which will equip you with the skills necessary to undertake further biomedical research. This project will open up new avenues in research into the role of integrins in the development of insulin resistance and diabetes in humans, potentially leading to new therapeutic strategies for these conditions.

This project has been shortlisted for a Norwich Research Park Studentship.  Suitable applicants will be interviewed as part of the Studentship Competition.  The interview dates will be the 10 and 11 January 2013. 

All students recruited onto this programme will be expected to undertake a three months internship during the second or third year of their degree. The internship will offer exciting and invaluable experience of work in an area outside of research, and full support and advice will be provided by a professional team from the UEA.
 

1. van der Flier, A. and Sonnenberg, A. (2001) Function and interactions of integrins. Cell Tissue Res. 305:285-298.
2. Guilherme, A. and Czech, M.P. (1998) Stimulation of IRS-1-associated phosphatidylinositol 3-kinase and Akt/protein kinase B but not glucose transport by beta1-integrin signaling in rat adipocytes. J. Biol. Chem. 273:33119-33122.
3. Delcommenne, M, Tan, C., Gray, V. et al. (1998) Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc. Natl. Acad. Sci. U.S.A. 95:11211-11216.
4. Kang, L., Ayala, J.E., Lee-Young, R.S. et al. (2011) Diet-induced muscle insulin resistance is associated with extracellular matrix remodelling and interaction with integrin α2β1 in mice. Diabetes 60:416-426.
5. Feral, C.C., Neels, J.G., Kummer, C. et al. (2008) Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Diabetes 57:1842-1851.