Prof Geoff Holman
Profile
Current Research
Structural studies. Mammalian tissues are known to express different glucose transporter isoforms (GLUTs 1-13) in different tissues. We are currently studying the structural differences and features of these isoforms that give rise to divergent function. Using molecular biology and cell biology approaches, glucose transporter constructs and mutants are being investigated which are impaired in glucose transport catalysis and altered subcellular trafficking and targeting.
Hexose analogues. The substrate specificity and functional properties of the GLUTs are being explored using a range of synthetic hexose analogues. Some of the GLUTs have high affinity for D-glucose (for example, GLUTs 1,3 and 4) while others (for example GLUT5 ) transport D-fructose preferentially. In addition, photoaffinity labels are being synthesised that can be used for studying the functional properties of each of the GLUTs.
Regulation of glucose transporter subcellular trafficking by insulin. Insulin has been shown to give a 20-fold increase in glucose transport into adipose cells. The mechanism of stimulation initially involves the tyrosine kinase activity of the insulin receptor and the enzyme phosphatidylinositol 3-kinase. Down-steam processes arising from these initial signalling events are being studied with particular emphasis on how signalling can influence the subcellular trafficking of glucose transporters. Photoaffinity sugar analogue probes are being used to study the insulin-dependent subcellular trafficking of the glucose transporter between intracellular and plasma membranes. The molecular basis of the impaired insulin signalling and glucose transporter translocation in pathophysiological conditions of insulin resistance, as occurs in Type II diabetes, are being investigated.
Goal: To determine the mechanisms involved in glucose transport catalysis and stimulation of glucose transport by insulin.
Publications
Koumanov, F., Pereira, V. J., Whitley, P. R. and Holman, G. D., 2012. GLUT4 Traffic through an ESCRT-III-Dependent Sorting Compartment in Adipocytes. PLoS ONE, 7 (9), e44141.
Holman, Geoff, 2012. Reagent. C07H19/20 -WO2012049464 (A1), 19 April 2012.
Betts, J. A., Thompson, D., Richardson, J. D., Chowdhury, E. A., Jeans, M., Holman, G. D. and Tsintzas, K., 2011. Bath Breakfast Project (BBP) - Examining the Role of Extended Daily Fasting in Human Energy Balance and Associated Health Outcomes: study protocol for a randomised controlled trial [ISRCTN31521726]. Trials, 12, 172.
Koumanov, F., Richardson, J. D., Murrow, B. A. and Holman, G. D., 2011. AS160 phosphotyrosine-binding domain constructs inhibit insulin-stimulated GLUT4 vesicle fusion with the plasma membrane. Journal of Biological Chemistry, 286 (19), pp. 16574-16582.
Lawrence, S. P., Holman, G. D. and Koumanov, F., 2010. Translocation of the Na+/H+ exchanger 1 (NHE1) in cardiomyocyte responses to insulin and energy-status signalling. Biochemical Journal, 432 (3), pp. 515-523.
Fazakerley, D. J., Holman, G. D., Marley, A., James, D. E., Stockli, J. and Coster, A. C. F., 2010. Kinetic evidence for unique regulation of GLUT4 trafficking by insulin and AMP-activated protein kinase activators in L6 myotubes. Journal of Biological Chemistry, 285 (3), pp. 1653-1660.
Stöckli, J., Fazakerley, D. J., Coster, A. C. F., Holman, G. D. and James, D. E., 2010. Muscling in on GLUT4 kinetics. Communicative & Integrative Biology, 3 (3), pp. 260-262.
Karlsson, H. K. R., Chibalin, A. V., Koistinen, H. A., Yang, J., Koumanov, F., Wallberg-Henriksson, H., Zierath, J. R. and Holman, G. D., 2009. Kinetics of GLUT4 trafficking in rat and human skeletal muscle. Diabetes, 58 (4), pp. 847-854.
Fazakerley, D. J., Lawrence, S. P., Lizunov, V. A., Cushman, S. W. and Holman, G. D., 2009. A common trafficking route for GLUT4 in cardiomyocytes in response to insulin, contraction and energy-status signalling. Journal of Cell Science, 122 (5), pp. 727-734.
Sakamoto, K. and Holman, G. D., 2008. Emerging role for AS160/TBC1D4 and TBC1D1 in the regulation of GLUT4 traffic. American Journal of Physiology: Endocrinology and Metabolism, 295 (1), E29-E37.
Holman, G. D. and Sakamoto, K., 2008. Regulating the motor for GLUT4 vesicle traffic. Cell Metabolism, 8 (5), pp. 344-346.
