Journal of PJ Martens et 

al. Arresting or curing type 1 249:2 T1–T11

Endocrinology diabetes

THEMATIC REVIEW
100 YEARS OF INSULIN

Arresting or curing type 1 diabetes: an elusive

goal, but closing the gap

Pieter-Jan Martens, Conny Gysemans and Chantal Mathieu

Clinical and Experimental Endocrinology (CEE), KU Leuven, Leuven, Belgium

Correspondence should be addressed to C Mathieu: chantal.mathieu@uzleuven.be

This paper forms part of a special section on 100 years of insulin. The guest editors for this section were James Cantley & Decio Eizirik

Abstract
Type 1 diabetes is one of the most common chronic diseases in children and Key Words
adolescents, but remains unpreventable and incurable. The discovery of insulin, already ff type 1 diabetes
100 years ago, embodied a lifesaver for people with type 1 diabetes as it allowed the ff beta cell
replacement of all functions of the beta cell. Nevertheless, despite all technological ff biomarkers
advances, the majority of type 1 diabetic patients fail to reach the recommended ff heterogeneous
target HbA1c levels. The disease-associated complications remain the true burden of ff immunotherapy
affected individuals and necessitate the search for disease prevention and reversal. The
recognition that type 1 diabetes is a heterogeneous disease with an etiology in which
both the innate and adaptive immune system as well as the insulin-producing beta cells
intimately interact, has fostered the idea that treatment to specific molecular or cellular
characteristics of the patient groups will be needed. Moreover, robust and reliable
biomarkers to detect type 1 diabetes in the early (pre-symptomatic) phases are wanted
to preserve functional beta cell mass. The pitfalls of past therapeutics along with the
Journal of Endocrinology
perspectives of current therapies can open up the path for future research. (2021) 249, T1–T11

Introduction
The year 2021 will celebrate the 100th anniversary of the
clinical use of insulin. This embodied a lifesaver for people
living with type 1 diabetes (T1D), the most common
chronic disease in children and young adolescents. But it
is not a cure, it is merely a part of our attempts to replace
all functions of the beta cells that are destroyed in T1D.
This means that therapy is based on symptom control
with glucose monitoring and administration of insulin
according to algorithms based on food intake, exercise
and other external factors. In many people with T1D,
tight glycemic control remains an elusive goal, resulting
in long-term micro- and macrovascular complications,
but also acute complications like hypoglycemic
attacks, episodes of severe hyperglycemia and diabetic
ketoacidosis. As a result, despite major advances in tools
to measure glucose levels and insulin therapy, life years
are still lost due to T1D. At present, people with T1D are
often treated with insulin analogs and use continuous
glucose monitoring systems that can even be integrated
with sensors and insulin pumps (i.e. hybrid closed-loop
systems) resulting in important steps forward in therapy.
Despite these technical advancements, the hope of
prevention and a cure for T1D remains. The fact that this
has not been achieved to date, is not for a lack of trying.

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In the process, important lessons have been learned. Here,
we describe some of these lessons and open up the path
for future research.
Type 1 diabetes: a mistake of the
insulin-producing beta cells, the immune
system or both?
The dogma that the immune system in T1D mistakenly
destroys healthy insulin-producing beta cells in the
pancreas, leading to absolute insulin deficiency (Atkinson
& Eisenbarth 2001), is being challenged in recent years.
Dr Bottazzo in 1986 and Dr Atkinson in 2016 debated
the question: 'Death of a beta cell: homicide or suicide?'
(Bottazzo 1986, Atkinson et  al. 2011). The definitive
answer remains unknown, but both sides have strong
arguments.
The classic hypothesis, first introduced by Dr
Eisenbarth in 1986, proposes that in an individual with a
predisposing genetic risk (mostly carried by specific types
of major histocompatibility complex (MHC) or human
leucocyte antigen (HLA) genes), activation of the immune
system by one or multiple environmental triggers results in
a rapid destruction of the pancreatic beta cells (Eisenbarth
1986). This implies a malfunction of the immune system
as the culprit. The discovery of pancreatic islet cell
autoantibodies (ICA), appearing in the period between
immune activation and the onset of clinical symptoms,
proved to be a landmark discovery in two important
aspects. First, it provided a method to predict the onset
of diabetes. Furthermore, as different autoantigens (i.e.
insulin, glutamic acid decarboxylase (GAD), protein
tyrosine phosphatase (IA-2 or ICA512), zinc transporter 8
(ZnT8) and tetraspanin) were discovered, it became clear
that beta cell-specific proteins and peptide fragments were
targeted by the immune system (Bonifacio 2015). Another
strong argument that the immune system may be the
causing factor in T1D came from the early observation
that transplantation of non-T cell-depleted bone marrow
precipitated diabetes (Lampeter et al. 1993).
In this hypothesis, as T1D is due to the aberrant
recognition of autoantigens, the most likely cause would
be a failure of central tolerance. However, as thymic
involution occurs in mammals at puberty, this would imply
that T1D would only occur prior to or soon after puberty
(Wagner 2016). Moreover, thymic selection appears to be
quantitatively similar between healthy individuals and
those with T1D (Culina et al. 2018). Yet, there seems to be a
major qualitative difference, as thymus-derived regulatory
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T cells (Tregs) are amongst the primary regulators of T1D
(Holohan et  al. 2019). Translational errors have been
described as a potential source of antigenic peptides to
which central immune tolerance is lacking, but to which
cytotoxic T cells in the circulation of T1D patients are
present, causing destruction of the insulin-producing beta
cells (Kracht et  al. 2017). In addition to mishaps in the
central immune system, in T1D, the peripheral immune
regulation appears defective as T cell receptor (TCR)
revision increases the T cell repertoire in the periphery.
Especially CD40-expressing CD4+ T cells alter their TCR
repertoire to become auto-aggressive (Wagner 2016,
Vaitaitis et al. 2017). Moreover, beta cell-specific CD8+ T
cells are present in equal numbers in the peripheral blood
of healthy individuals and T1D patients but are found
exclusively in the pancreas of T1D patients (Skowera
et  al. 2015, Culina et  al. 2018). Yet, despite numerical
correlates, the phenotypic profile looks different in T1D
with hallmarks of an antigen-driven expansion of beta
cell-specific CD8+ T cells (Skowera et  al. 2015). This
observation is supported by the exhaustion of these CD8+
T cells in slow disease progressors (Wiedeman et al. 2020).
Another argument is that the HLA region, which enables
antigen recognition by antigen-presenting cells, confers
the greatest contributor to the genetic susceptibility of
T1D (Mathieu et al. 2018).
If, on the other hand, abnormal pancreatic beta cells
would be the culprit, it would imply a normal function
of the immune system as it then needs to clear these
dysfunctional cells. In this perspective, T1D etiology
becomes comparable to effective anti-tumor immunity.
Several arguments support a primary defect in insulin-
producing beta cells. First, recent observations suggest
smaller pancreatic volumes in those affected or at risk
of T1D (Campbell-Thompson et  al. 2019, Virostko et  al.
2019). Second, clear signs of beta cell stress can be detected
in those on their way to develop T1D, as illustrated by
an increased proinsulin-to-insulin ratio (Wasserfall et  al.
2017). This increased ratio suggests abnormalities in
insulin processing and vesicular trafficking (Rodriguez-
Calvo et  al. 2017). Moreover, non-specific triggers, like
increased metabolic demand or viral infections, have
been shown to stress beta cells, inducing endoplasmic
reticulum (ER) stress and have been associated with
T1D (Eizirik et  al. 2013). ER stress eventually results in
components of the folding process being hampered,
initiating the unfolded protein response (UPR) in order to
optimize the folding capacity of the ER. However, if this
is unsuccessful, the beta cell is marked as dysfunctional
and apoptosis is set in motion. However, UPR by itself
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has the potential to trigger an inflammatory response
that attracts immune cells and initiates the entire cascade
leading to T1D (Eizirik et  al. 2013). Moreover, ER stress
may again increase the visibility of the beta cells to the
immune system (Thomaidou et  al. 2020). Therefore,
ER stress constitutes a major contributory factor to
beta cell dysfunction in early T1D (Eizirik et  al. 2013).
As hyperglycemia stresses the beta cells even further,
this may result in a vicious circle, as was proven by the
observation that the decline in beta cell function was less
in intensively insulin-treated T1D patients (The Diabetes
Control and Complications Trial Research Group 1998).
The argument of ER stress as an etiologic factor of T1D
was reinforced by the observation that in a T1D animal
model, the non-obese diabetic (NOD) mouse, avoidance
of ER stress resulted in T1D protection (Engin et al. 2013).
In this 'beta cell centric hypothesis', once the beta
cell is under attack, a cascade is set into motion, as
this inflammatory environment seems to result in the
release of additional pro-inflammatory cytokines and
chemokines by the beta cells, thus attracting more cells of
the immune system (Cardozo et al. 2003). Interestingly, in
the presence of inflammation, beta cells overexpress HLA
class I molecules creating an additional homing beacon
for cytotoxic T cells (Richardson et al. 2016). Recently, it
has been shown 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 for the immune system. These neo-antigens can
even cause epitope spreading in the immune reaction,
as demonstrated by the presence of antibodies against
these neo-epitopes in people with T1D (James et al. 2018).
Inflamed beta cells can furthermore release exosomes
(containing, i.e. proinsulin, GAD65, and IA-2), which
also have the potential to trigger autoimmune responses
(Cianciaruso et  al. 2017). A final argument pointing to
the beta cell as the true culprit is the fact that current
immunotherapies are able to only temporarily slow the
decline in beta cell function, suggesting that residual
pathogenic mechanisms remain untargeted (Mallone &
Eizirik 2020).
Most probably the answer lays in the middle,
with T1D being the result of a complex network of
dysfunctions both in the beta cell and the immune
system, with defects in both innate and adaptive immune
regulation, creating ‘the perfect storm’ (Peters et al. 2019).
An example of how both sides of the story are connected
in T1D is demonstrated by genetic polymorphisms
within a single locus encoding the transcription factor
basic leucine zipper transcription factor 2 (BACH2).
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First identified as a key regulator of Tregs, it was thought
to be yet another argument of a deficient immune system
in T1D (Roychoudhuri et  al. 2013). Later, it was shown
that BACH2 has an essential anti-apoptotic role in the
protection of the insulin-producing beta cells against
the cytokine-mediated killing (Marroqui et  al. 2014). It
appears that BACH2 is moreover downregulated by pro-
inflammatory cytokines, resulting in a chain of events in
beta cells, already under immune assault (Marroqui et al.
2014). Therefore, downregulation of BACH2 may result in
both a failing beta cell and immune system, or just be the
result of evolving T1D. This illustrates the complexity of
the pathogenesis of T1D (Fig. 1).
Type 1 diabetes is a heterogeneous disease
Despite T1D always resulting in the same clinical
endpoint of insulin deficiency and requiring lifelong
exogenous insulin substitution, it is actually a collective
term of a heterogeneous disease. Clinicians recognize this
heterogeneity, with some people being diagnosed early in
life, others late in life; some being isolated cases, others
having a family history of T1D; some having T1D in the
context of multiple autoimmune diseases, others having
just T1D; some losing all C-peptide (reflecting functional
beta cell mass) in a few months, while others preserving
it life-long.
At present, over 60 loci are associated with an
increased susceptibility to T1D, with the HLA region as a
major contributor (Bakay et al. 2019). The ever-expanding
number of associated loci supports the heterogeneity of
T1D with, as discussed above, some genes linked to beta
cell dysfunction and others to immune cell dysfunction.
The genetic complexity is illustrated by the fact that
despite the 15-fold increase in the risk of T1D in individuals
having a first-degree relative with T1D, the majority of
new T1D diagnoses are made in individuals having no
known family history for T1D (Pociot & Lernmark 2016).
In addition, many people carrying the highest risk HLA
haplotypes do not develop T1D (Skyler et al. 2017). These
data, together with the observation that the presentation
of T1D is changing, with rapid increases in T1D numbers
and a shift toward younger ages at disease diagnosis,
suggest the presence of external triggers that can differ
between different individuals. In an attempt to better
understand the nature of these environmental triggers,
The Environmental Determinants of Diabetes in the Young
(TEDDY) study was initiated. This is a large prospective
cohort study in children – beginning at birth, with high-
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Figure 1
The vicious circle of dying beta cells in type 1 diabetes and therapeutic opportunities to interfere at different disease stages. In a genetically predisposed
individual, undefined factor(s) (depicted in orange) will trigger type 1 diabetes by the induction of beta cell stress, leading to compensatory responses
that ultimately are deleterious for the beta cells, and by activation of inappropriate immune responses toward the beta cells (stage 0). Once pancreatic
beta cells are failing, a vicious circle advances as a result of the release of (neo)antigens and cytokines/chemokines (stages 1–2), reinforcing the ongoing
autoimmune responses and contributing to (complete) destruction of functional pancreatic beta cells (stage 3). The constant interaction between beta
cells and immune system may vary in individuals at risk, leading to disease heterogeneity. As this destruction process is highly immunogenic, it is by itself
a trigger to reinitiate this cascade in adjoining (so far) healthy islets. This figure again emphasizes the need for the identification of robust and reliable
biomarkers (depicted in green) as their implementation would offer an opportunity to detect type 1 diabetes in early disease stages, resulting in a better
efficacy of therapeutics. Therapeutic approaches (depicted in purple) can be designed for each disease stage. As to date, none has shown prevention or
long-term disease reversal, indicating that lasting prevention and/or cure will depend on combination therapies. GAD, glutamic acid decarboxylase;
GADA, glutamic acid decarboxylase antibodies; IA-2A, tyrosine phosphatase-related islet antigen 2; IAA, insulin autoantibodies.

risk genotypes – aiming to identify environmental factors
that influence islet autoimmunity and T1D onset (TEDDY
Study Group 2008). Yet, despite all these efforts, predicting
T1D in a reliable way remains a challenge as a recent 8-year
progress report showed that although risk factors can be
associated with islet autoimmunity and T1D, they are not
precise predictors (Krischer et al. 2019).
At present, the best predictor of progression toward
T1D in genetically predisposed individuals, but also in
the general population, is the presence of autoantibodies
(Primavera et  al. 2020). An array of autoantibodies has
been described, with heterogeneity in their appearance.
Whereas in children insulin autoantibodies (IAA) are most
prevalent, in adults GAD autoantibodies (GADA) are the
most frequent ones. Again, heterogeneity exists, as the
risk depends on antibody titer, affinity, immunoglobulin
subclasses and target epitopes on single or multiple
islet autoantigens (Bonifacio & Achenbach 2019).
Therefore, when using islet autoantibodies in the
prediction of T1D onset, it is important to understand
their implication. Prospective birth-cohort studies in
high-risk children, including the BABYDIAB, DIPP, DAISY
and TEDDY trials, have provided major insights into
the meaning of antibody appearance in the evolution
toward symptom onset. Mostly, T1D evolution starts with
the appearance of one autoantibody. This is possible as
early as 3 months of age, peaking at the age of 9 months
(Krischer et  al. 2015). IAA or GADA are most frequently
the first autoantibodies, appearing a median period of
7 months before the second autoantibody. Yet, the rate
of progression is highly dependent on the hierarchy of
antibody appearance (Vehik et al. 2020), with a consensus
that the positivity of two or more islet autoantibodies
confers a high risk of developing symptomatic T1D
(Insel et  al. 2015). In longitudinal studies, only 15% of
children with one islet autoantibody developed T1D
within 10 years, compared to 70% of those with at least
two islet autoantibodies (Ziegler et  al. 2013). The 30%
of high-risk patients that do not progress to T1D within
10 years are termed 'slow progressor' (Long et  al. 2018).
To complicate things even more, even reversion of islet
autoantibody positivity (seroconversion) is possible
(Vehik et al. 2016). The islet autoantibodies epitomize the
disease heterogeneity of T1D as according to which islet

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autoantibody appears first and possibly even disappears;
the aggressiveness of the autoimmune response can be
predicted. Thus, although autoantibodies are at present
the ‘best biomarker’, finding better biomarkers is a priority
on the path to T1D prevention or cure (see below).
Heterogeneity also exists in the functional pancreatic
beta cell mass both at T1D onset and during disease
progression (Campbell-Thompson et al. 2016). A general
observation is that children lose their functional beta
cell mass, as measured by C-peptide, more rapidly than
adults do. Some individuals with longstanding T1D
retain measurable levels of serum C-peptide and harbor
insulin-positive islets in their pancreas even decades after
diagnosis (Keenan et al. 2010, Wasserfall et al. 2017). Some
arguments exist to suggest that in some individuals beta
cells can proliferate, be generated from ductal cells or
transdifferentiate from other islet cells like alpha cells, but
no clear explanation is available for the heterogeneity of
beta cell mass (Saunders & Powers 2016, Lam et al. 2017).
Finally, also in the infiltration type around the beta
cells (i.e. insulitis) heterogeneity can be seen. Whereas
initiatives like nPOD show that most individuals with
T1D have only subtle infiltration, in contrast to the
observations on massive infiltration in the NOD mouse,
heterogeneity in the composition of the infiltrate has been
described (Atkinson et  al. 2020). Recently, two distinct
profiles, according to the proportion of CD20+ B cells,
were observed in the immune infiltrate, related to the age
of the person and the rate of beta cell loss. The proportion
of B cells in the immune infiltrate and the associated rate
of beta cell loss was higher in younger patients (diagnosed
before the age of 7 years) and lower in older patients
(diagnosed after the age of 13 years) (Leete et  al. 2016).
The same pattern of two distinct profiles was also detected
in the peripheral blood as both pro-inflammatory (defined
by multi-autoantibody and interferon-(IFN)-γ positivity)
and controlled (defined by pauci-autoantibody and
interleukin (IL)-10 positivity) responses were observed
in newly diagnosed T1D patients (Arif et  al. 2014). This
translates to younger patients having approximately
10–15% of residual insulin-containing islets at the time
of T1D diagnosis to 40% in older patients (Leete et  al.
2016). Moreover, it implicates a significant role of beta
cell dysfunction rather than death in these patients.
Lessons learned from intervention studies
Why have we not cured T1D yet? Our plea starts by saying
that we have not tried our very best. This is supported
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by the dazzling list of studies already performed in
people with new-onset T1D or unaffected high-risk
family members. Large consortia have been established
worldwide to perform multicenter trials. Examples are the
Type 1 Diabetes TrialNet (an in 2001 established National
Institutes of Health (NIH)-funded and Juvenile Diabetes
Research Foundation (JDRF)-supported international
clinical trial network that emerged from the Diabetes
Prevention Trial Type 1 (DPT-1)) and the more recent
INNODIA consortium (a European partnership between
academic institutions, industrial partners and patient
organizations) (Mathieu 2018). Most interventions to
date have either targeted the immune system (by general
or specific immune suppression or modulation), or were
based on strategies aimed at the induction of tolerance
toward proteins or peptides relevant to T1D.
Non-antigen-specific immunotherapy, based on
immunosuppression, is the oldest of these approaches.
Cyclosporine A was the first drug to show the ability
to induce disease remission in people with new-onset
T1D. However, it was also the first to expose the major
obstacles associated with this strategy, namely disease
recurrence and adverse effects associated with systemic
immunosuppressive drugs (reviewed in Flores et  al.
2019). A flurry of immune-modulatory agents has been
tested that allowed drawing important conclusions. As
such, it has become apparent that anti-inflammatory
interventions, targeting single cytokines (like TNF-α
or IL-1) are not successful in T1D (Donath et  al. 2019).
In a recent meta-analysis, it was demonstrated that of
all interventions, two are by far the most successful in
preventing functional beta cell decline: anti-thymocyte
globulin (ATG) and teplizumab (anti-CD3 antibody)
(Jacobsen et al. 2020).
ATG is an old immune modulator widely used
in organ transplantation. However, the doses of ATG
that proved to be effective in delaying beta cell loss in
new-onset T1D patients were lower than those used
for transplantation. Indeed, higher doses (6.5 mg/kg)
were not effective in contrast to low doses (2.5 mg/kg)
(Gitelman et  al. 2016, Haller et  al. 2019). A possible
explanation for the protective effect of the low dose is
that low doses cause a transient T cell depletion followed
by T cell reconstitution, resulting in a shift toward
tolerance induction as demonstrated by an increase in
Tregs (Lu et al. 2011).
Teplizumab fits in the concept of using more specific
anti-T cell antibodies in this T cell-mediated autoimmune
disease. First used in animals in 1988 and a first-in-
men trial (safety testing) already in 1989, the story of
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anti-CD3 monoclonal antibodies is a prime example of
the importance of choosing the correct study protocol
and endpoints (reviewed in Chatenoud 2019). After all, it
started as a success story showing complete and permanent
remission of T1D in animals. The initial clinical trials
using humanized anti-CD3 monoclonal antibodies (i.e.
teplizumab or the aglycosylated otelixizumab) were
encouraging, showing preservation of beta cell function
(Herold et  al. 2002, Keymeulen et  al. 2005). Large phase
III trials for both should have been the icing on the
cake, but failed. For otelixizumab, this was the DEFEND
trial and was unsuccessful most probably as a result of
the decision to reduce the dose to 15 times less than
the one previously proven to be effective (Ambery et  al.
2014, Aronson et al. 2014). It was later suggested that the
maximum target engagement was only achieved at a dose
6 times higher than the one used in the original DEFEND
trial, but it was the end of otelixizumab (Vlasakakis et al.
2019). The large phase III trial for teplizumab was the
PROTÉGÉ trial and also failed. This time, the probable
reason for failing was the study population and the choice
of the endpoint (insulin requirement) (Sherry et al. 2011).
Later, the AbATE trial chose its endpoints more wisely
and was able to demonstrate that teplizumab preserved
C-peptide in people with new-onset T1D with even up
to 7 years after diagnosis a reduced decline in C-peptide
in responders (Hagopian et  al. 2013, Perdigoto et  al.
2019). Predicting the response to teplizumab remains
challenging and underlines the complexity of T1D and
the need for biomarkers of therapeutic success. Still, the
early start of therapy (at a moment when more beta cells
are still present) positively impacted therapeutic response
(Herold et al. 2013). Furthermore, responders were shown
to express a class of partially exhausted T cells (defined by
the expression of EOMES and inhibitory factors like TIGIT
and KLRG1) (Long et  al. 2017). The signs of exhaustion
might serve as a signature of prevention of disease
deterioration. Moreover, the induction of exhaustion
was also demonstrated to be a hallmark in distinguishing
slow and fast disease progressors (Wiedeman et al. 2020).
Recently, aiming to preserve even more pancreatic
beta cells, teplizumab was given to non-diabetic, high-
risk relatives of people with T1D (defined by two or more
diabetes-related autoantibodies – stage 2) and this was
able to delay progression to symptom onset in T1D up to
3 years (Herold et al. 2019, Sims et al. 2020).
The final goal in T1D is the re-establishment of antigen-
specific tolerance. Thus, many trials have been conducted
in an attempt to introduce T1D-relevant antigens to induce
specific tolerance. Some of these trials have used insulin
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administered orally or GAD in aluminium hydroxide
(alum) administered subcutaneously (Beam et  al. 2017).
Despite the fact that none demonstrated convincingly
beta cell protection, the major lesson learned from these
trials is that the antigen-specific interventions tested were
safe (Roep et al. 2019). To obtain superior antigen-based
tolerance induction, trials have been designed to combine
antigen therapy with low-grade immune modulation. For
proinsulin, based on successful animal trials (Takiishi
et  al. 2017, Cook et  al. 2020), this is the ongoing study
by Precigen ActoBio, combining teplizumab with AG019
Actobiotics™, an oral capsule consisting of genetically
engineered Lactococcus lactis, modified to deliver human
proinsulin together with the tolerance inducing cytokine
human IL-10 (clinical trial identifier: NCT03751007,
EudraCT 2017-002871-24).
As GAD in alum administered subcutaneously did
not result in convincing results, this concept was revived
in the DIAGNODE-1 trial, designed to administer GAD
in alum into lymph nodes (a more targeted approach),
but also in combination with vitamin D for low-grade
immunomodulation (Tavira et  al. 2018). Based on
relatively promising results, GAD in alum is now being
tested in combination with ibuprofen (DIABGAD;
clinical trial identifier: NCT01785108), etanercept
(EDCR; clinical trial identifier: NCT02464033), or GABA
(GABA/Diamyd; clinical trial identifier: NCT02002130)
as anti-inflammatory component. To elucidate the
immunomodulatory role of vitamin D in DIAGNODE-1,
further research is ongoing (clinical trial identifier:
NCT03345004).
Road to a cure – need for biomarkers
As the majority of pancreatic beta cell destruction happens
during the pre-symptomatic stage, this emphasizes that
therapeutic approaches should preferentially start during
the pre-symptomatic period (Atkinson & Eisenbarth
2001). To date, the standard biomarkers are genetic
markers and autoantibodies. Genetic biomarkers in T1D
are mainly based on HLA typing with the highest HLA-DR
and -DQ, that is HLA-DR3/4 and HLA-DQ8, genotypes
present in 30–40% of T1D individuals, increasing
the risk over 10-fold compared to the background
population (present in 2–3%) (Mathieu et  al. 2018).
Autoantibodies are, as described above, robust biomarkers
only useful for discriminating T1D from other types of
diabetes and by itself predict an increased risk for T1D as
the significance of the presence of ICA is dependent on
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the a priori probability of a true result (e.g. genetic high-
risk individual) (Bonifacio & Achenbach 2019).
This highlights the need for true biomarkers in T1D
and makes it the major focus of research in INNODIA.
Over 50 clinical centers in Europe, both pediatric and
adult clinics, are collecting samples from new-onset T1D
patients and from unaffected family members of people
living with T1D. In a natural history study, spanning
several years, modular interrogation platforms for 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
immunomes and RNA analyses. INNODIA is in the final
stages of performing an integrated multi-omics natural
history study on samples of new-onset T1D individuals.
Of importance, these biomarker analyses are also included
in the clinical trials running in the INNODIA network,
thus not only opening the path to biomarkers of disease,
but also raising hope for the discovery of biomarkers of
therapeutic effect and success of interventions.
Based on the observations described above, suggesting
a role in the pathogenesis of T1D for both the beta cells
and the immune system, interventions with the highest
probability of success should be based on combinations of
interventions. The most straightforward is as previously
described the combination of immune modulation with
antigen-based tolerance induction. Other appealing
combinations would be agents improving beta cell health
together with immune modulators. As such, a recent
study combined liraglutide, a GLP-1 receptor agonist and
an antibody targeting the cytokine IL-21. Results were
intriguing, with additive effects observed during therapy,
but all effect was lost after stopping the agents (Von
Herrath et al. 2020).
To reduce inflammation at the onset, anti-
inflammatory drugs may be added to the treatment
regimens. A combination of abatacept and rituximab
is currently being tested in T1D prevention (stage 2)
(clinical trial identifier: NCT03929601, UC4DK117009),
as both abatacept and rituximab were shown to slow the
decline of beta cell function in new-onset T1D, driven by
an effect seen early after treatment initiation (Pescovitz
et  al. 2009, Orban et  al. 2011). However, not always
does a combination therapy result in a better efficacy as
demonstrated by the addition of pegylated granulocyte
colony-stimulating factor (GCSF) to low-dose ATG, which
seemed to diminish the benefits provided by low-dose
ATG (Haller et al. 2019).
The Achilles heel in the design of novel studies is the
lack of strong animal models for T1D to guide clinical trial
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Arresting or curing type 1 249:2 T7
diabetes
design together with the long duration and large sample
size needed for robust clinical trial design. Here, adaptive
trial designs on the backbone of a master protocol may
be the answer. In INNODIA, a Master Protocol has been
designed that will be the guide for all studies in INNODIA,
allowing comparison between studies and allowing
adaptive trial design (Dunger et  al. 2020). As such, the
INNODIA Master Protocol uses the same inclusion criteria,
visit schedule, duration, sample collection for standardized
efficacy and mechanistic studies throughout all studies.
The inclusion/exclusion criteria can be adapted to the
requirements of specific interventions, but the clinical
and mechanistic evaluations remain largely unchanged,
providing the primary outcomes and the potential for
a more detailed analysis of variability in intervention
response. Additional study visits and sample collection
allow studies of toxicology and pharmacokinetic or
dynamic analyses. Appealing in T1D to drive progress
are adaptive trial design strategies such as dose finding,
dropping study arms, inclusion of additional treatments,
options to share controls and potentially inclusion of data
from the natural history studies.
Trials should be conducted in the most relevant
populations: young adults, adolescents and in particular
children. We must admit that by drawing conclusions
on interventions in adults, where the course of the
disease is very different from that in children (see part on
heterogeneity), we may be missing some interventions that
could have worked in children. Thus, we, as researchers and
clinicians, need to convince regulators and industry that
even early-phase trials should be conducted in children,
of course, taking into account all possible safety measures.
Finally, a robust definition of therapeutic success is
needed. This definition may be different at different stages
of the disease: in people with just a genetic risk, success
could be the prevention of autoimmunity (defined by
prevention of biomarker appearance, e.g. autoantibodies)
whereas in people with new-onset T1D success could
be prevention of decline in functional beta cell mass as
measured by stimulated C-peptide. In the latter group,
the presence of C-peptide is associated with fewer
complications in the long-term and a smoother glycemic
control in the immediate term.
Conclusion
Type 1 diabetes is one of the most common and severe
chronic diseases in children, adolescents and young adults,
and in desperate need of disease-modifying therapy. For
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 Journal of PJ Martens et al.
Endocrinology
100 years now, the gold standard treatment consists of
lifelong insulin treatment with the aim to maintain a
normal glucose homeostasis. The discovery of insulin was
pioneering, transforming T1D from a quickly fatal disease
to an incurable, chronic disease. However, as the majority
of T1D patients fail to reach recommended target HbA1c
levels, the burden of disease-associated complications
remains important. This should stimulate the search for
disease-modifying therapies. As this review describes, we
have already traveled a long way, but the road remains
long and full of obstacles, the most important being the
unidentified culprit of T1D (beta cell or immune system or
both). Moreover, even if we can identify the culprit, we still
need to discover the exact mechanism that sets everything
in motion. Nevertheless, progress in our understanding is
made and results of clinical intervention trials are promising,
showing a temporary deferral of disease onset or transient
preservation of functional beta cell mass (as defined by
C-peptide) by several interventions. Temporary or transient
mostly means a couple of months to even a couple of years,
but for now, to many people living with T1D these carefree
couple of months to years already mean a lot.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of this review.
Funding
This work did not receive any specific grant from any funding agency in
the public, commercial or non-profit sector that could be perceived as
prejudicing the impartiality of the research reported.
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Received in final form 12 November 2020

Accepted 9 March 2021
Accepted Manuscript published online 16 March 2021

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