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[18]
insulin processing and vesicular trafficking . Moreover, non-specific triggers associated with T1D, such as
increased metabolic demand or viral infections, have been shown to induce endoplasmic reticulum (ER)
[19]
stress and thereby stress beta cells . This results in a vicious cycle, as ER stress may again increase the
visibility of the beta cells to the immune system, thereby initiating further destruction of non-affected
islets . Indeed, a beta cell under attack results in the release of additional pro-inflammatory cytokines and
[20]
[21]
chemokines by the beta cells and, as such, attracts even more cells of the immune system . Moreover, beta
cells overexpress HLA class I molecules, creating an additional homing beacon for cytotoxic T cells .
[22]
Whereas both the immune-mediated and the beta cell-centric hypothesis hold their ground, T1D is most
likely the result of a complex network of dysfunctions in both the beta cells and the immune system .
[23]
Interestingly, this is demonstrated, among others, in the observation that stressed beta cells not only misfold
insulin but also misprocess other proteins and peptides, leading to the formation of neo-antigens generating
novel epitopes . These novel epitopes by themselves then result in an aberrant immune response as they
[24]
[25]
are believed to trigger the peripheral activation of CD4+ and CD8+ autoreactive T lymphocytes .
All these different hypotheses [Figure 1] are not only scientifically intriguing but also probably the reason
for the limited success of interventions pursuing an arrest of beta cell destruction. Indeed, interventions
attempting the restoration of immune tolerance using antigen-specific therapies have failed, and pure
immune suppression or modulation has only succeeded in temporarily delaying the decline of functional
[26]
beta cell mass . These failed interventions also triggered the belief that T1D is a heterogeneous disease,
where in some, the immune system may be the causal factor (and then still different immune cell types may
be prominent in the attack), whereas in others, more beta cell defects are responsible for the final beta cell
disappearance.

TYPE 1 DIABETES: SEARCH FOR BIOMARKERS
The presence of islet-specific autoantibodies, not only in genetically predisposed individuals but also in the
[27]
general population, remains the best predictor of progression towards T1D . Nevertheless, the application
of islet-specific autoantibodies as a predictor of T1D is not ready for daily clinical practice. One of the main
issues remains the extent of heterogeneity, with the risk of T1D depending on the antibody titer, affinity,
immunoglobulin subclasses, and target epitopes on single or multiple islet autoantigens . Insulin
[28]
autoantibodies (IAA) and GAD autoantibodies (GADA) are most frequently the first appearing
autoantibodies, with a higher prevalence of the former in children and the latter in adults . Moreover, the
[29]
presence of only one islet autoantibody is not sufficient to determine the evolution towards T1D. In a
prospective cohort study, only 15% of children with one islet autoantibody developed T1D within 10 years,
compared to 70% of those with at least two islet autoantibodies . A recent study showed that autoantibody
[10]
appearance usually happened before six years of age, with optimal screening ages for initial islet
autoantibody screening in children at two and six years of age . Therefore, the consensus states that only
[30]
[31]
the positivity of at least two islet autoantibodies confers a high risk of developing symptomatic T1D .

As the above-mentioned tackles the obstacles in the use of islet-specific autoantibodies as a biomarker, the
quest for novel biomarkers is on. Novel biomarkers can contribute to a more precise prediction of disease, a
better understanding of the heterogeneity of the disease, and predict or at least measure the response to
therapy. In INNODIA (Innovative Medicines Initiative of the European Commission; www.innodia.eu), a
public–private partnership, over 50 clinical centers in Europe, both pediatric and adult clinics, are collecting
samples from new-onset T1D patients and unaffected family members of people living with T1D. In a
natural history study spanning several years, modular interrogation platforms for the analysis of cellular and
molecular features of beta cell and immune cell biomarkers have been established. These include proteomes,
lipidomes, and metabolomes, as well as a full immunome and RNA analyses. A highly standardized