Two siblings who have the only known mutations in a key gene anywhere in the world have helped scientists gain new insights that could advance the search for new treatments for type 1 diabetes.

Type 1 diabetes (also known as autoimmune diabetes) is a devastating and life-long disease in which the patient’s immune cells wrongly destroy the insulin-producing beta cells in the pancreas. People living with autoimmune diabetes need to test their blood sugar and inject insulin throughout their lives to control their blood sugars and prevent complications.

Autoimmune diabetes with clinical onset in very early childhood is rare and can result from a variety of genetic variants. However, there are many cases of early onset diabetes without known genetic explanation. In addition, some cancer patients treated with a category of immunotherapy known as immune checkpoint inhibitors — which target the same pathway that the mutation was found in — are prone to developing autoimmune diabetes. The reason why only this category of cancer immunotherapy can trigger autoimmune diabetes is not well understood. Like type 1 diabetes, genetic or immunotherapy-associated autoimmune diabetes requires life-long insulin replacement therapy — there is currently no cure.

The new research, published in the Journal of Experimental Medicine, began when researchers studied two siblings who were diagnosed with a rare genetic form of autoimmune diabetes in the first weeks of life. The University of Exeter offers free genetic testing worldwide for babies diagnosed with diabetes before they are nine months old. For most of these babies, this service provides a genetic diagnosis and in around half of these babies, it allows for a change in treatment.

When researchers tested the two siblings in the study, no mutation in any of the known causes was identified. The Exeter team then performed whole genome sequencing to look for previously unknown causes of autoimmune diabetes. Through this sequencing, they found a mutation in the gene encoding PD-L1 in the siblings and realised it could be responsible for their very-early-onset autoimmune diabetes.

Study author Dr Matthew Johnson, from the University of Exeter, UK, said: “PD-L1 has been particularly well studied in animal models because of its crucial function in sending a stop signal to the immune system and its relevance to cancer immunotherapy. But, to our knowledge, nobody has ever found humans with a disease-causing mutation in the gene encoding PD-L1. We searched the globe, looking at all the large-scale datasets that we know of, and we haven’t been able to find another family. These siblings therefore provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans.”

The PD-L1 protein is expressed on many different cell types. Its receptor, PD-1, is expressed exclusively on immune cells. When the two proteins bind together it provides a stop signal to the immune system, preventing collateral damage to the bodies tissues and organs.

Researchers from the Rockefeller Institute in New York and King’s College London joined forces with Exeter to study the siblings, with funding from Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK, and the US National Institutes for Health. After contacting the family’s clinician in Morocco, the Exeter team visited the siblings where they were living to collect samples and return them to King’s College London, within the crucial ten-hour window for analysis while the immune cells were still alive. The London and New York teams then performed extensive analysis on the siblings’ cells.

Study co-author Dr Masato Ogishi, from the Rockefeller University in New York, said: “We first showed that the mutation completely disabled the function of PD-L1 protein. We then studied the immune system of the siblings to look for immunological abnormalities that could account for their extremely early-onset diabetes. As we previously described another two siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity including autoimmune diabetes and extensive dysregulation in their immune cells, we expected to find severe dysregulation of the immune system in the PD-L1-deficient siblings. To our great surprise, their immune systems looked pretty much normal in almost all aspects throughout the study. Therefore, PD-L1 is certainly indispensable for preventing autoimmune diabetes but is dispensable for many other aspects of human immune system. We think that PD-L2, another ligand of PD-1, albeit less well-studied than PD-L1, may be serving as a back-up system when PD-L1 is not available. This concept needs to be further investigated in the context of artificial blockade for PD-L1 as cancer immunotherapy.”

Study co-author Professor Timothy Tree, from King’s College London, said: “Through studying this one set of siblings – unique in the world to our knowledge – we have found that the PD-L1 gene is essential for avoiding autoimmune diabetes, but is not essential for ‘everyday’ immune function. This leads us to the grand question; ‘what is the role of PD-L1 in our pancreas making it critical for preventing our immune cells destroying our beta cells?’ We know that under certain conditions beta cells express PD-L1. However, certain types of immune cells in the pancreas also express PD-L1. We now need to work out the “communication” between different cell types that is critical for preventing autoimmune diabetes.

“This finding increases our knowledge of how autoimmune forms of diabetes such as type 1 diabetes develop. It opens up a new potential target for treatments that could prevent diabetes in the future. Simultaneously, it gives new knowledge to the cancer immunotherapy field by uniquely providing the results of completely disabling PD-L1 in a person, something you could never manipulate in studies. Reducing PD-L1 is already effective for cancer treatment, and boosting it is now being investigated as a type 1 diabetes treatment – our findings will help accelerate the search for new and better drugs.”

Dr Lucy Chambers, Head of Research Communications at Diabetes UK, said: “Pioneering treatments that alter the behaviour of the immune system to hold off its attack on the pancreas are already advancing type 1 diabetes treatment in the USA, and are awaiting approval here in the UK.

“By zeroing in on the precise role of an important player in the type 1 diabetes immune attack, this exciting discovery could pave the way for treatments that are more effective, more targeted and more transformational for people with or at risk of type 1 diabetes.”

A new study interviewed endocrinologists to find what works and what doesn’t

Senior author Stephanie Crossen uses telehealth.  CREDIT UC Regents

Grocery stores, airports, and beaches aren’t great places for telehealth visits with your endocrinologist. But home can be one of the best locations. A doctor can gain helpful insights into a patient’s home environment, which can positively impact their care.

This is just one finding shared in a new study published this week in The Journal of Clinical Diabetes.

Researchers interviewed clinicians and staff who provide diabetes care through telehealth at four University of California academic medical centers: UC Davis Health, UCSF Health, UCLA Health, and UC San Diego Health. They asked open-ended questions to learn how telehealth is used, the challenges faced, helpful practices, and plans for the future.

“These are critical and timely questions since telehealth remains an important way to provide care in the wake of the COVID-19 pandemic. But there is limited data about how to optimize it for specific types of care,” said Stephanie Crossen, UC Davis pediatric endocrinologist and senior author of the study. “We asked the people who have the most experience in this area to identify best practices which can be used, further studied, and refined moving forward.”

The study suggests several important strategies to improve telehealth operations:

1. Dedicated staff support is essential to obtain data from patients’ devices (like remote glucose monitors) ahead of telehealth visits. This can improve access to care for individuals with limited digital literacy, save clinician time during visits and prevent unnecessary rescheduling of appointments.
2. Efficient workflows around scheduling follow-up visits are needed to ensure people don’t experience lapses in care.
3. Finding the best ways to facilitate team-based diabetes care is key. For a diabetes management telehealth visit, this may include a nurse, dietitian, social worker, pharmacist or educator, in addition to the primary clinician. It is important to create workflows that support this effort.

Interviewees also said telehealth visits can provide a good opportunity to review and discuss the impact of the home environment on diabetes self-care. Through screen sharing, clinicians can also review trends in a patient’s glucose data and discuss daily management successes or challenges.

Finally, those interviewed also noted the need for clear patient guidelines about appropriate timing and physical setting for joining telehealth visits to make them efficient and effective. For example, visits while driving or at a large group event were not advised.

“I hope the findings of our study will spark discussion around how we can optimize telehealth and take advantage of its unique capabilities to improve patient care, rather than trying to replicate the in-person visit,” said Sarah Haynes, assistant professor from the UC Davis Department of Pediatrics and lead author of the study.