Project Reference: TRG27-IMS-DF1

Project title: Uncovering the molecular machinery that tunes whole-body insulin-stimulated glucose disposal

Project outline

After a meal, the hormone insulin helps to lower blood glucose by encouraging muscle and fat cells to take up glucose from the blood. These cells increase glucose uptake by rapidly moving the glucose transporter, GLUT4, to the cell surface. How the insulin signal is communicated within these cells, and how the underlying membrane trafficking machinery is tuned, is still only partly understood. This is a fundamental question about how living cells sense environmental signals and translate it into a coordinated response that is critical for whole body energy homeostasis.

In recent years, our lab has found specific genetic and pharmacological interventions that can tune this pathway to be more or less sensitive, enhancing or blocking insulin-stimulated GLUT4 delivery. This project uses these tools to uncover the machinery that couples the insulin signal to glucose uptake, and, importantly, to test how this works in different cell types (fat, muscle) and in the whole animal.

The student will: (1) identify the proteins and regulatory events linking insulin signalling to GLUT4 delivery, using cell-based trafficking assays and quantitative proteomics; (2) determine how this machinery sets the magnitude and speed of the insulin response; (3) test physiological relevance in vivo, asking whether tuning the pathway alters tissue glucose uptake and whole-body insulin sensitivity, including in diet-induced insulin resistance, using state-of-the-art methods to manipulate gene expression in distinct fat depots and muscles.

Training will span cell culture (adipocyte, myocyte), quantitative imaging and GLUT4-translocation assays, mass-spectrometry proteomics and data analysis, and in vivo metabolic phenotyping. 

Principal Supervisor

Dr Daniel Fazakerley

Email address: djf72@cam.ac.uk

Department / Partner Institute: Institute of Metabolic Science (IMS)

Website: https://www.mrl.ims.cam.ac.uk/staff/dr-daniel-fazakerley

BBSRC strategic theme

Understanding the rules of life