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Antibody treatment - a gatekeeper to insulin resistance

Project summary

Severe insulin resistance is a key feature of a rare form of diabetes, caused by genetic changes which affects the structure of the insulin receptor. Dr Gemma Brierley will explore whether antibodies can be redesigned to improve the function of the insulin receptor. This research could improve our understanding of how a rare form of diabetes develops and and lead to life-saving new treatments. 

Background to research

Insulin resistance is a key feature of type 2 diabetes - but a severe form of insulin resistance also results from changes to the gene for the insulin receptor. 

Cells such as our muscle, liver and fat cells have a structure on their surfaces called the ‘insulin receptor’. The job of the insulin receptor is to pick up insulin molecules and bring them inside our cells, so that glucose can be taken up from the blood. If the receptor is damaged insulin can’t be taken up properly. 

An extremely rare type of diabetes occurs when babies inherit a non-working form of this gene from each parent.  At the moment there aren’t any effective treatments and many children with this form of diabetes die young.  

Dr Gemma Brierley and her team previously found that antibodies can be used to cause small changes to how the insulin receptor works – changes that lowered blood sugar levels in mice. The problem was that the antibodies did not drop off the insulin receptors once inside the cells, meaning the receptors were not free to return to the cell surface to repeat this process. Dr Gemma Brierley wants to improve the design of these antibodies, so that the insulin receptors can be recycled again and again. 

Research aims

Dr Gemma Brierley will see how changes to the gene for the insulin receptor can be combated by improving the design of these antibodies. The researchers know that, in order to work properly, the antibodies must drop off the receptors once they enter our cells. 

They’ll make antibodies which have been changed in many ways and will test to see if they work like insulin on the cells and allow the receptor to come back to the cell surface. Once they have found the best antibodies, they will test them on cells in the lab and in mice. 

They will then make many different insulin receptors to simulate the many genetic problems that can impact a person’s insulin receptor and test to see if the antibodies work on each of these. Doing this will help doctors to decide quickly whether children diagnosed with receptor problems may benefit from this potential treatment. 

Potential benefit to people with diabetes

If successful, this research will overcome a barrier to development of antibodies as potentially life-saving treatments for children born with a rare type of diabetes. The findings will also help us understand why people with a rare form of diabetes don’t respond properly to insulin (insulin resistance). In the future, this knowledge could help scientists to find better ways to treat the insulin resistance directly at the site of the underlying problem – the insulin receptor – and lead to new treatments for more common types of diabetes too.  

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