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Page 2 of 11 Mathieu et al. Metab Target Organ Damage 2022;2:15 https://dx.doi.org/10.20517/mtod.2022.16

TYPE 1 DIABETES: AN AUTOIMMUNE DISEASE WITH A MAJOR ROLE FOR THE BETA
CELL ITSELF
Type 1 diabetes (T1D) is an immune-mediated disease in which the insulin-producing beta cells are
destroyed by the immune system, resulting in absolute insulin deficiency . The classic hypothesis states
[1]
that, in a genetically predisposed individual, activation of the immune system by one or multiple
environmental triggers results in rapid destruction of the pancreatic beta cells . More recently, attention is
[2]
shifting towards malfunction of the pancreatic beta cells as a trigger of the immune response, albeit in a
genetically at-risk individual . This stresses the importance of genetics in T1D.
[3]

With already over 60 loci associated with increased susceptibility to T1D, some genes are linked to beta cell
dysfunction and others to immune cell dysfunction, with the HLA region being the major contributor .
[4,5]
The genetic complexity of T1D is illustrated by the fact that the majority of new T1D diagnoses are made in
individuals having no known family history of T1D, despite the 15-fold increased risk for T1D and 2-fold
increased risk for coexisting associated autoimmune diseases in individuals having a first-degree relative
[8]
[6,7]
with T1D . In addition, many people carrying the highest risk HLA haplotypes do not develop T1D .
However, HLA genes remain the basis of genetic risk prediction models in T1D. The Global Platform for
the Prevention of Autoimmune Diabetes (GPPAD) is a European platform that makes use of an enriched
genetic risk score (with 47 SNPs) in a general population of newborns to identify those individuals with a
[9]
25-fold increased risk of developing T1D (1.3% versus 0.4%, in a Western European background) .

The trigger of how T1D occurs in a genetically at-risk individual remains to be elucidated. For years, the
immune system was believed to be the only culprit. This issue is from studies in animal models of T1D, such
as the NOD mouse that spontaneously develops a disease very similar to T1D, as well as from the detection
of autoantibodies against several peptides and proteins of the beta cell in those with recently diagnosed
T1D. Moreover, the presence of these autoantibodies in the blood has been shown to have a predictive value
for the development of T1D in normoglycemic individuals. These observations were first made in first-
degree relatives (and thus genetically predisposed individuals), but they have been extended to the general
population. There is now evidence that the presence of two or more autoantibodies almost certainly predicts
the evolution to T1D in normoglycemic individuals . Typical autoantibodies are antibodies against
[10]
glutamic acid decarboxylase (GAD), protein tyrosine phosphatase (IA-2 or ICA512), zinc transporter 8
(ZnT8), and insulin itself . Although these autoantibodies are interesting biomarkers in the prediction of
[11]
the evolution to T1D, they most likely do not play a pathogenic role. When studying the pancreas of people
with T1D who died around the time of diagnosis, it is mainly a cellular infiltrate that is observed
[12]
(insulitis) . In animal models, the disease is transferred in immune compromised animals by immune cells
and not by antibodies . The immune cells responsible for the immune attack remain unknown. However,
[13]
despite the importance of HLA class II genes in the genetic predisposition, it is not the CD4+ T lymphocyte
[14]
but rather the HLA class I restricted CD8+ T lymphocyte that is implicated in direct beta cell destruction .
However, many other immune cell types could play a role, with an emerging role for innate or non-
lymphocyte cells, such as NK cells or neutrophils.

An interesting alternative hypothesis poses that T1D is the result of a dysfunctional beta cell that is cleared
by a correctly functioning immune system. In this perspective, T1D etiology becomes comparable to
effective anti-tumor immunity and is not classified as an autoimmune disease. Arguments favoring this
hypothesis point to a primary defect in insulin-producing beta cells as the initial trigger. This is supported
by recent observations suggesting smaller pancreatic volumes in those affected or at-risk of T1D [15,16] .
Furthermore, clear signs of beta cell stress can be detected in those on their way to developing T1D,
exemplified by an increased proinsulin-to-insulin ratio . This increased ratio suggests abnormalities in
[17]