King's College London

The project will focus on developing an in vitro model of glucose metabolism and insulin resistance in skeletal muscle, with the aim of understanding genetic and environmental factors that cause type 2 diabetes.

The project is one of 36 projects that have received funding in the first round of the UKRI’s new cross research council responsive mode pilot scheme. The scheme supports new and creative ideas emerging from the research community that span disciplines.

Dr Lieberam’s project (titled ‘Developing a human-iPSC skeletal muscle model of glucose metabolism on responsive elastomer nanofibers’) will involve elements of molecular biology, biochemistry/metabolism and biotechnology. The project will be carried out in partnership with Professor Wenhui Song, University College London, and Dr Daniel Fazakerley, the University of Cambridge. The £1.2m award will be split between the three applicants.

Understanding insulin resistance

Diabetes UK reports that 4.4 million people in the UK have diabetes, with around 90% of those having type 2 diabetes.¹ In type 2 diabetes, the body either doesn’t make enough of the hormone insulin or doesn’t respond properly to the insulin it does produce (known as insulin resistance).

Insulin controls the level of sugar in our blood by instructing cells – mainly muscle cells – to take up glucose after a meal. Without insulin, blood sugar levels can get dangerously high. Insulin injections are used to manage type 1 diabetes, where the body can’t produce insulin, but these injections become ineffective over time for people with insulin-resistant type 2 diabetes.

To better understand the biology of insulin resistance, the new project will focus on developing a cellular model that can be used to study how muscle cells respond to insulin in the laboratory.

As a starting point, the team will adapt a model it created to study neuromuscular disease to investigate the regulation of glucose uptake in skeletal muscle. The model will be made from nerve cells that relay signals from the brain to muscle (called motor neurons) and muscle fibres (also known as myofibers) derived from a type of human stem cell. The two cell types will be cultured together in multi-well microdevices, along with scaffolds made of aligned nanofibers to support the myofibers, and tiny sensors to detect glucose levels.

To mimic the effects of diabetes in the model, the team will stop glucose transport in the muscle cells by editing their genetic codes to contain mutations that cause type 2 diabetes in humans. They will also expose the muscle cells to chemicals that can lead to insulin resistance, like saturated fatty acids which are found in many foods.

In his lab at King’s, Dr Lieberam will genetically modify the myofibers with a fluorescent tag. The tag will allow the team to track and image the movement of an important transporter protein called GLUT4, which takes up glucose into cells in response to insulin.

The model, which will be the first of its kind in diabetes research, will be a valuable resource for studying insulin responses in skeletal muscle and the failure of these processes in diabetes. The team will also explore the viability of the model as a platform for testing drugs to regulate glucose uptake.

References

¹Diabetes UK. How many people in the UK have diabetes? Available at: diabetes.org.uk/about-us/about-the-charity/our-strategy/statistics (accessed September 2024).