A rare genetic mutation recently discovered by researchers could provide key clues to preventing diabetes

British researchers at the University of Exeter have made a breakthrough discovery: a unique genetic mutation identified in two baby siblings that has never before been seen in humans, opening the way to new treatment options for diabetes type 1.

The mutation is in the gene for a protein called PD-L1 (programmed cell death ligand 1) which act as a kind of “brake” to keep the body’s immune responses in check.

The new study explains how the protein may be responsible for the autoimmune form of diabetes that children developed at a very young age.

“We’ve looked around the globe, looking at all the large-scale data sets we know of, and we haven’t been able to find another family,” says molecular geneticist Matthew Johnson, from the University of Exeter.

“Therefore, these siblings give us a unique and incredibly important opportunity to investigate what happens when this gene is turned off in humans.”

Type 1 diabetes is also known as autoimmune diabetes because of how the body’s built-in immune system attacks the pancreatic beta cells, stopping normal insulin production.

People with this condition must inject insulin regularly to manage their blood sugar levels.

The two brothers, aged 10 and 11 at the time of the study, developed diabetes in the first weeks of life.

A closer look at the immune cells present in the two children confirmed that their unique genetic mutation prevented the PD-L1 protein from working properly.

Since PD-L1 and its receptor PD-1 combine as a sort of safety mechanism to keep the immune system in check, and cancer treatments that block PD-L1 functions can also lead to diabetes, it appears that the PD-L1 protein has a key role in preventing type 1 diabetes.

However, in a surprising twist, it turned out that the immune systems of the two young brothers were functioning quite normally, even without the regulation of the immune system that PD-L1 and PD-1 normally provide.

“We believe that PD-L2, another ligand of PD-1, although less studied than PD-L1, could serve as a backup system when PD-L1 is not available,” says researcher Masato Ogishi of the University Rockefeller of New York.

A key conclusion the researchers reached is that the PD-L1 protein is essential for preventing type 1 diabetes, but not as important for keeping many other functions of the immune system normal.

The clues provided by the discovery of this genetic mutation, plus the link between cancer treatment and diabetes, could help unlock new ways to tackle type 1 diabetes – if researchers can learn how PD-L1 prevents it and how PD-L2 act as a backup solution.

“We now need to find out what is the communication between different cell types that is essential for preventing autoimmune diabetes,” says immunologist Timothy Tree of King’s College London in the UK.

“This finding increases our knowledge of how autoimmune forms of diabetes, such as type 1 diabetes, develop and points to a potential new target for treatments that could prevent diabetes in the future,” the authors of this finding concluded.

The research was recently published in Journal of Experimental Medicine – JEM.