DRWF Research: From the tiniest patients come the biggest clues
How a rare form of childhood diabetes is shedding light on beta cells – and the future of diabetes care.
Imagine being told your newborn baby has diabetes. For a small number of families, this is a heartbreaking reality.
However, in some cases, the diabetes disappears within a few months – only to potentially return years later. This rare form of the condition is known as transient neonatal diabetes mellitus (TNDM) and, in a major step forward in diabetes research, it is offering scientists unexpected new insights into how insulin-producing cells develop and function – and what might go wrong in all forms of diabetes.
Thanks to funding from DRWF, a new study led by James Russ-Silsby and his team at the University of Exeter has discovered a brand-new genetic cause of TNDM. Their findings, now under review at a leading scientific journal, shed light not only on this rare condition but also on the fundamental biology of diabetes itself.
This is the first new gene to be linked to TNDM in over a decade – and what it is revealing about the development of insulin-producing beta cells could have far-reaching implications for diabetes research and treatment.
What is transient neonatal diabetes mellitus?
Neonatal diabetes is a condition where diabetes appears in the first six months of life. Unlike type 1 diabetes, which is caused by the immune system attacking insulin-producing cells, neonatal diabetes is almost always genetic. In about half of cases, the diabetes is transient, meaning it goes away after a few months. However, it can return later in childhood or adulthood.
The rarity of the condition makes it difficult to study, but understanding the genetic causes of neonatal diabetes can unlock vital clues about how insulin production works – and what can go wrong. This is why James’s research has been so exciting.
The breakthrough a decade in the making
Until now, only eight genes had been linked to transient neonatal diabetes.
Most were discovered more than 10 years ago, and in recent years progress had slowed. But the Exeter research team has now identified a ninth gene, called PAX4, as a previously unknown cause of the condition.
The breakthrough came after genome sequencing was performed on 18 children with TNDM and their parents, creating a detailed map of the genetic information passed down in each family. In two unrelated families, the researchers found “spelling mistakes” (or mutations) in both copies of the PAX4 gene – mutations that completely shut the gene down.
Previous studies in test models had already shown that deleting PAX4 leads to a complete loss of pancreatic beta cells and a corresponding increase in alpha cells, which produce glucagon.
However, until now, there had been no confirmed reports of people born without functioning PAX4 genes. The discovery of two unrelated children with this exact genetic change provided the first clear human evidence of PAX4’s essential role in the development of insulin-producing cells.
What the discovery tells us
What is especially intriguing is that despite losing PAX4, these children still managed to develop some insulin-producing beta cells – enough for their diabetes to be temporary. It suggests that, in humans, the total loss of PAX4 does not entirely prevent the development of beta cells, unlike in test models. This difference offers new insight into the unique ways in which human beta cells form and mature – and may help explain why diabetes takes different forms in different people.
To dig deeper, the Exeter team collaborated with experts at the Translational Genomics of Diabetes Lab at Stanford University in California, US to look at what PAX4 does in lab-grown beta cells. Using a technique called CUT&RUN sequencing, they mapped out the DNA regions controlled by PAX4 in these cells.
They found that the gene acts as a kind of master controller, regulating other genes that are essential for beta cell development and for releasing insulin in response to sugar in the blood. In short, PAX4 is critical not just for making beta cells, but for helping them function properly – making it hugely relevant to understanding all forms of diabetes.
How this helps real families
For the two children identified in the study, this research has already had direct benefits. They now have a clear genetic diagnosis – something that can be crucial for planning future treatment, monitoring for recurrence, and offering reassurance and information to families.
It also means that PAX4 can now be added to genetic testing panels used to diagnose neonatal diabetes. This will help identify other children with this rare subtype, giving them and their families access to early diagnosis, and more targeted monitoring and treatment later in life.
Beyond diagnosis, the discovery also offers long-term potential for improving diabetes therapies. By revealing how PAX4 helps build and regulate beta cells, the research adds to the growing body of knowledge that underpins efforts to regenerate or replace these cells in people with diabetes. For example, stem cell therapies aimed at creating new beta cells could be improved by better understanding how genes like PAX4 shape their development.
A second genetic clue: A shared mystery region
In addition to the PAX4 discovery, the team also identified a mysterious shared stretch of DNA in three families with neonatal diabetes – a “haplotype” on chromosome 19 not found in public databases. While they have not yet pinpointed the exact gene responsible, it is highly likely that this region contains another undiscovered cause of neonatal diabetes, and the team is already applying for funding to continue this search.
Meanwhile, the PAX4 work has been submitted for publication and recently shared at major diabetes conferences, including the 2024 EASD Minkowski Award Lecture and the 2025 Diabetes UK Professional Conference. This ensures the findings are reaching both the scientific community and the public – and highlights the importance of continued investment in rare disease research.
Looking ahead
The work conducted by James and his colleagues not only met the goals set out at the beginning of the research programme – it exceeded them. As well as identifying PAX4 as a novel cause of TNDM and mapping its role in beta cell development, the team has laid the groundwork for future discoveries and diagnostic improvements.
The findings have already been shared with the scientific community through presentations at major conferences, and a paper describing the work has been submitted to the journal Molecular Metabolism. A preprint version is available online, making the results immediately accessible to researchers worldwide.
While this study focused on a rare condition, its impact extends far beyond the few families affected. By helping to unlock the secrets of beta cell formation, this research contributes to a broader understanding of diabetes and brings us one step closer to better treatments.
This study may have started with a handful of rare cases – but it is ending with insights that could benefit millions.
By uncovering a new gene involved in insulin production, James’s team is helping to rewrite our understanding of how diabetes begins, and how it might one day be stopped.
DRWF Pump Priming Awards
James Russ-Silsby was one of six DRWF Pump Priming research award recipients for 2024, who collectively received £119,982 for their study projects.
The DRWF research programme is designed to support bright young researchers, as well as established institutions, as they strive to make the kind of life-changing breakthrough our diabetes community is hoping for.
Since the first DRWF research awards were made in 1999, the charity has committed more than £13 million to diabetes research in the UK and around the world.
James received £20,000 for the study entitled Gene discovery in transient neonatal diabetes to gain new insights into beta cell development and function.
James said: “The aim of our project is to provide a deeper understanding of how beta cells function and develop. We will study individuals with rare types of diabetes caused by a single genetic defect.
“Our findings will provide key new information on the pathways that govern beta cell function and development. This is the crucial first step towards identifying new drug targets for diabetes, bringing us a step closer to better management and treatment of this condition.”
Angela Shore, Chair of the DRWF Research Advisory Board, on James’s final report: “James has delivered on the original aims and outcomes of the project and made further discoveries.
“It is extremely impressive to have not only identified a new cause of transient neonatal diabetes – that of homozygous PAX4 variants in two cases – but also to have worked internationally to identify some potential functional pathways by which the genetic variants may cause diabetes.
“The further identification of a rare shared 3.5-megabase haplotype on chromosome 19 in two individuals with TNDM and one with permanent diabetes is very exciting and is an opportunity for James and colleagues to find further genetic causes of neonatal diabetes.
“James should be congratulated on being asked to present his work in the Early Career Investigator session at Diabetes UK. He will also present to the European diabetes community at the EASD (European Association for the Study of Diabetes) conference in September. I was delighted to see that he engaged with the DRWF Wellness Day where he presented his research. I wish James well in his future discoveries and remind him (and his colleagues) to continue to publicly acknowledge the DRWF funding which enabled him to make these important findings.”
Read more about DRWF Research here
This article originally appeared in the Autumn 2025 edition of Diabetes Wellness News. To subscribe visit here
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