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Institute of Metabolic Science

Metabolic Research Laboratories
 

Research Interests 

We are interested in understanding how hormones and environmental cues regulate cell metabolism, with a specific focus on insulin-regulated glucose transport into fat and muscle cells.   

One of the ways in which insulin lowers blood glucose is through stimulating glucose transport into adipose and muscle tissue. Insulin activates a signal transduction cascade in these tissues to promote the translocation of the glucose transporter GLUT4 from specialised intracellular storage vesicles to the plasma membrane, facilitating glucose uptake. We currently have an incomplete understanding of the signalling events and trafficking processes that control the redistribution of GLUT4. One of the objectives of our work is to fill in these knowledge gaps. 

The reason we want to increase our understanding in this area is that impaired insulin-stimulated glucose transport in muscle and fat is a major contributor to whole body insulin resistance – a state where insulin no longer efficiently lowers blood glucose and a risk factor for type 2 diabetes. There is currently no consensus on the molecular basis for impaired insulin responses in these tissues, and there are no treatments that specifically target this pathway. We aim to shed light on how the insulin signalling network and GLUT4 trafficking apparatus are altered in insulin resistance, and identify new therapeutic targets. 

Research Approach 

We take an interdisciplinary approach using cell culture and in vivo models to study insulin action, GLUT4 trafficking and glucose metabolism. We take hints from ‘omics (human genetics, proteomics) data to find novel genes/proteins that play a role in insulin action, insulin-stimulated GLUT4 trafficking and/or insulin resistance. 

We have established methods to screen many genes-of-interest for roles in specific metabolic processes. For example, we assay insulin-stimulated endogenous GLUT4 translocation using high-content imaging, and continue to develop new ways to study distinct aspects of GLUT4 trafficking (e.g. delivery to the cell surface, internalisation). We use our expertise in molecular (e.g., manipulating gene expression) and cell biology (e.g., microscopy) and biochemistry (e.g., subcellular fractionation, immunoprecipitation) to study how proteins-of-interest regulate insulin responses and the GLUT4 pathway in health and disease. 


Group Members

Dr Delia Cicciarello, Research Associate

Dr Dilip Menon, Research Associate

Eleanor Fox, PhD Student


Research Funding 

MRC project grant 

UKRI Cross Council Research Grant

Wellcome Discovery Award

Publications

Key publications: 

Tan J, Kunzmann GB, Virtue S, Cantor JR, Fazakerley DJ. Seeing the world through the eyes of cultured cells. Cell Metab. 2025 Apr 1;37(4):802-805. doi: 10.1016/j.cmet.2025.01.027.

Gaugel J, et al.. Picalm, a novel regulator of GLUT4-trafficking in adipose tissue. Mol Metab. 2024 Oct;88:102014. doi: 10.1016/j.molmet.2024.102014.

Baird HJM, Shun-Shion AS et al. A quantitative pipeline to assess secretion of human leptin coding variants reveals mechanisms underlying leptin deficiencies. J Biol Chem. 2024 Jul 11:107562. doi: 10.1016/j.jbc.2024.107562

Tan J, Virtue S, Norris DM, et al. Limited oxygen in standard cell culture alters metabolism and function of differentiated cells. EMBO J. 2024 Jun;43(11):2127-2165. doi: 10.1038/s44318-024-00084-7

Williamson A et al. Genome-wide association study and functional characterization identifies candidate genes for insulin-stimulated glucose uptake. Nat Genet. 2023 Jun;55(6):973-983. doi: 10.1038/s41588-023-01408-9.  

van Gerwen J, Shun-Shion AS, Fazakerley DJ. Insulin signalling and GLUT4 trafficking in insulin resistance. Biochem Soc Trans. 2023 Jun 28;51(3):1057-1069. doi: 10.1042/BST20221066. 

Fazakerley DJ, van Gerwen J et al. Phosphoproteomics reveals rewiring of the insulin signaling network and multi-nodal defects in insulin resistance. Nat Commun. 2023 Feb 18;14(1):923. doi: 10.1038/s41467-023-36549-2

Diaz-Vegas A, Norris DM et al. A high-content endogenous GLUT4 trafficking assay reveals new aspects of adipocyte biology. Life Sci Alliance. 2022 Oct 25;6(1):e202201585. doi: 10.26508/lsa.202201585.  

Calejman CM, Doxsey WG, Fazakerley DJ, Guertin DA. Integrating adipocyte insulin signaling and metabolism in the multi-omics era. Trends Biochem Sci. 2022 47(6):531-546. 

Fazakerley DJ, Koumanov F, Holman GD. GLUT4 On the move. Biochem J. 2022 479(3):445-462. 

Assistant Professor,IMS-MRL
Course Director for the MPhil in Obesity, Endocrinology and Metabolism