Type 1 diabetes may not, after all, be a single disease. A large-scale genetic study, conducted by teams from the United States of America (USA) and the United Kingdom, has found differences suggesting the existence of two biologically distinct conditions, determined by a genetic marker already known for its association with the development of the disease.
Type 1 diabetes is an autoimmune disease. The immune system, which should protect the body, begins to attack the beta cells of the pancreas, which are responsible for producing insulin. When these cells are destroyed, the body loses the ability to properly regulate blood glucose levels.
Researchers have long known that two genetic patterns, known as HLA-DR3 and HLA-DR4, are associated with a higher risk of developing type 1 diabetes. It was also already known that the first signs of the disease can vary depending on which of these patterns is present.
What remained was a fundamental question: were these clinical differences merely different manifestations of the same disease, or did they reflect truly different biological mechanisms?
In search of that answer, a team of scientists carried out the first genome-wide association study, known by the acronym GWAS, to analyse separately people with type 1 diabetes according to these two genetic signatures.
Published in the scientific journal Diabetologia, the research analysed genetic data from 9,091 people with type 1 diabetes and compared them with those of 14,157 healthy people, used as a control group.
Two routes to the same disease
The results revealed genetic differences between the groups associated with HLA-DR3 and HLA-DR4 that were large enough for the researchers to consider the possibility that they were dealing with distinct subtypes of type 1 diabetes.
The scale of this genetic separation particularly caught the team's attention. According to the researchers, the difference found between DR3-associated diabetes and DR4-related diabetes is comparable to that observed between schizophrenia and bipolar disorder — two psychiatric illnesses that may share certain characteristics but are considered genetically distinct.
The analysis also revealed a potentially decisive difference: the immune system mechanisms involved appear not to be exactly the same.
Among people with the HLA-DR3 profile, the genetic signals point to a more significant involvement of mast cells. These immune system cells are associated with allergies and inflammatory processes and normally act as the body's sentinels against certain threats, including infections.
In the HLA-DR4 group, however, the picture is different. Here, T lymphocytes play a greater role. These immune cells attack other cells directly when activated and are among those chiefly responsible for destroying the insulin-producing cells of the pancreas.
The destination may therefore be similar — the development of type 1 diabetes — but the biological route to the disease seems to vary according to each person's genetic profile.
Why does the discovery matter?
The distinction between these possible subtypes could have important consequences both for patients and for scientific research. Identifying different mechanisms within a disease makes it possible, on the one hand, to move towards more personalised treatments and, on the other, to design studies better able to distinguish the response of different groups of patients.
According to the authors of the paper, quoted by Science Alert, if type 1 diabetes can develop through different biological pathways, it may also make sense for these differences to be taken into account when choosing and evaluating treatments.
One example is clinical trials. In future, studies of new diabetes drugs could analyse separately the results obtained in participants with the DR3 profile and in those with DR4. Until now, this separation has rarely been made.
The discovery also paves the way for monitoring patients over time in light of their genetic signature, relating it to the appearance and evolution of autoantibodies and to different environmental exposures.
It does not yet mean, however, that type 1 diabetes has been definitively divided into two diseases. The researchers themselves warn that the results will have to be confirmed by further studies.
The evidence now found nevertheless points to a possibility with relevant implications: what currently receives a single clinical designation may conceal different biological processes. If this distinction is confirmed, type 1 diabetes could move towards a more precise classification — and, eventually, towards treatments designed according to each patient's genetic and biological profile.
