Biomedicine & Pharmacotherapy 170 (2024) 115958

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Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Targeting IL-12 family cytokines: A potential strategy for type 1 and type 2
diabetes mellitus
Jiayu Luo 1, Tingting Ning 1, Xing Li , Tao Jiang , Shenglong Tan , Dandan Ma *
Department of Endodontics, Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong Province, China

A R T I C L E I N F O A B S T R A C T

Keywords: Diabetes is a common metabolic disease characterized by an imbalance in blood glucose levels. The pathogenesis
Diabetes mellitus of diabetes involves the essential role of cytokines, particularly the IL-12 family cytokines. These cytokines,
IL-12 family cytokines which have a similar structure, play multiple roles in regulating the immune response. Recent studies have
Therapeutic targets
emphasized the importance of IL-12 family cytokines in the development of both type 1 and type 2 diabetes
Pathogenesis
mellitus. As a result, they hold promise as potential therapeutic targets for the treatment of these conditions. This
Inflammation
Clinical application review focuses on the potential of targeting IL-12 family cytokines for diabetes therapy based on their roles in the
pathogenesis of both types of diabetes. We have summarized various therapies that target IL-12 family cytokines,
including drug therapy, combination therapy, cell therapy, gene therapy, cytokine engineering therapy, and gut
microbiota modulation. By analyzing the advantages and disadvantages of these therapies, we have evaluated
their feasibility for clinical application and proposed possible solutions to overcome any challenges. In conclu­
sion, targeting IL-12 family cytokines for diabetes therapy provides updated insights into their potential benefits,
such as controlling inflammation, preserving islet β cells, reversing the onset of diabetes, and impeding the
development of diabetic complications.

1. Introduction
Diabetes mellitus is a chronic metabolic disease characterized pri­
marily by hyperglycemia [1]. The prevalence of diabetes is expected to
reach 537 million worldwide in 2021, as reported by the International
Diabetes Association [1]. The two most common types of diabetes are
type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).
Despite considerable research, the mechanisms underlying T1DM and
T2DM are not yet fully understood. Various factors, including immune
disorders, contribute to the development of diabetes. Cytokines have
been extensively studied and are known to play a significant role in the
pathogenesis of both T1DM and T2DM.
In previous discussions, there has been extensive research on the role
of IL-12 in both T1DM and T2DM. However, the involvement of other
members of the IL-12 family, such as IL-23, IL-27, and IL-35, in the
pathogenesis of diabetes has not been fully reviewed. Unlike other
interleukin families, the IL-12 family of cytokines share common chains
and receptors, suggesting that their functions may overlap. These unique
structures and compositions give the IL-12 family cytokines dual roles in
promoting both pro- and anti-inflammation in diabetes. Therefore, it is
intriguing to investigate the functions and interactions of IL-12 family
cytokines in diabetes, considering their compositions and structures.
Currently, the treatment of T1DM and T2DM primarily focuses on
anti-hyperglycemic effects, such as insulin and sulfonylurea. However,
this approach often leads to uncontrolled inflammation in diabetes and
subsequent complications, including delayed wound healing,

Abbreviations: T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus; CTL, cytotoxic T lymphocytes; DCs, dendritic cells; PBMCs, peripheral blood
mononuclear cells; EBI3, Epstein–Barr virus-induced gene 3; IRF-1, interferon regulatory factor 1; Th0, naive CD4 + T helper cells; Th1, mature CD4+T helper cells;
ILCs, innate lymphoid cells; TFH, follicular helper T cells; mDCs, myeloid dendritic cells; NF-kB, Nuclear factor kappa-light-chain-enhancer of activated B cells;
NAFLD, non-alcoholic fatty liver disease; TLR, Toll-Like Receptors; FDA, Food and Drug Administration; JAK-STAT, Janus kinase-signal transducers and activators of
transcription; INGAP, insulin-resistant protein; LSF-LA, a combination of Lisofylline and Linoleic-acid self-assembled into micelles; AIRE, autoimmune Regulators;
CAR-T, Chimeric antigen receptors Tregs; MHC, major histocompatibility complex; Bregs, regulatory B cells; Tregs, regulatory T cells; IL-23R, IL-23 receptors;
Synthekines, synthesize cytokines.
* Corresponding author.
E-mail address: mdd@smu.edu.cn (D. Ma).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.biopha.2023.115958
Received 31 August 2023; Received in revised form 20 November 2023; Accepted 27 November 2023
Available online 7 December 2023
0753-3322/© 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
J. Luo et al.
retinopathy, neuropathy, and atherosclerosis. It has become increas­
ingly apparent that targeting cytokines involved in T1DM and T2DM is
crucial in controlling inflammation. Unfortunately, the clinical appli­
cation of cytokine targeting is limited due to low specificity. Therefore,
it is necessary to assess the therapeutic potential and obstacles associ­
ated with targeting IL-12 family cytokines for diabetes therapy.
In this review, we aim to explore the significant correlation between
IL-12 family cytokines and diabetes, focusing on their implications in the
development of T1DM and T2DM. Additionally, we provide a compre­
hensive overview of the current and potential therapeutic approaches
targeting IL-12 family cytokines. These include drug therapy, gene
therapy, cell therapy, combination therapy, cytokine engineering ther­
apy, and modulation of gut microbiota. By examining the advantages
and drawbacks of each therapy, we identify the existing barriers to the
application of cytokines and propose potential solutions for future
research. Overall, our objective is to offer valuable insights into the field
of diabetes therapy.
1.1. Immune disorders contribute to T1DM and T2DM
Type 1 diabetes mellitus (T1DM) is primarily an autoimmune disease
characterized by the involvement of CD4+ and CD8+ T cells, which play
a role in its pathogenesis [2]. In T1DM, the immune system mistakenly
identifies islet cells as foreign entities, leading to their attack by the
immune system [2]. This process is further exacerbated by the contin­
uous release of pro-inflammatory cytokines [3]. The complex cause of
immune disorders in T1DM may be closely associated with individual
susceptibility, with individuals carrying genetic variations in tumor
necrosis factor-alpha (TNF-α) being at a higher risk [4].
Type 2 diabetes mellitus (T2DM) is characterized by insulin resis­
tance and reduced insulin levels [5]. Although the exact mechanisms
underlying T2DM are still unclear, obesity is widely recognized as a
major risk factor. Obesity contributes to chronic low-grade inflamma­
tion by increasing the levels of pro-inflammatory cytokines such as
TNF-α and IL-6, while reducing the levels of protective factors like
adiponectin [6,7]. This inflammation-induced insulin resistance ulti­
mately leads to the development of T2DM [8]. To prevent the onset of
T2DM, it is crucial to disrupt the association between obesity and insulin
resistance through anti-inflammatory therapies.
Both T1DM and T2DM are influenced by an excessive inflammatory
response. This inflammatory response causes the activation of islet cells
in the pancreas through a mechanism involving the accumulation of pro-
inflammatory cytokines, ultimately leading to their caspase-dependent
activation or even apoptosis [9]. Specifically, IL-12 family cytokines
play a crucial role in exacerbating immune disorders in both T1DM and
T2DM.
1.2. Changes of IL-12 family cytokines in T1DM and T2DM
IL-12 family cytokines, which include IL-12, IL-27, IL-23, IL-35, and
IL-39, play crucial roles in immunoregulation [10,11]. These cytokines
share structural similarities and have overlapping functions. They are all
heterodimeric cytokines composed of two subunits. IL-12 and IL-23
share the same subunit, IL-12p40, while IL-27 and IL-35 share EBI3.
Besides, IL-35 and IL-12 share IL-12p35 as a subunit. These cytokines
bind to specific receptors and activate JAK-STAT signaling pathways
[12]. In terms of function, IL-12, IL-23, and IL-27 primarily promote
inflammation in both T1DM and T2DM. On the other hand, IL-35 and
IL-27 enable to counteract inflammation. It is important to note that
each member of the IL-12 family has distinct characteristics and con­
tributes to various aspects of T1DM and T2DM. The role of IL-39 in these
conditions remains to be explored in future research. Therefore, the
remainder of this discussion will focus on IL-12, IL-27, IL-23, and IL-35.
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Biomedicine & Pharmacotherapy 170 (2024) 115958
1.2.1. IL-12 family cytokines may serve as predictive indicators and reflect
the severity of T1DM and T2DM
IL-12 family cytokines appear to serve as warning signals in the body,
potentially providing insights into the onset of both T1DM and T2DM.
For instance, a decrease in circulating levels of IL-27 has been suggested
as a potential predictor for T2DM. It is established that insulin resistance
precedes the development of T2DM, and lower levels of circulating IL-27
have been found in individuals with insulin resistance, indicating that
IL-27 may serve as a predictive marker for T2DM [13]. This association
may be attributed to the disrupted regulation of adipocyte thermogen­
esis by IL-27, which can result in adipose accumulation and the subse­
quent development of T2DM [13].
Contrarily, elevated levels of circulating IL-27 have been linked to an
increased risk of T1DM. A Two-Sample Mendelian Randomization Study
demonstrated that higher circulating protein levels of EBI3 (a subunit of
IL-27) are associated with an enhanced risk of T1DM [14]. Furthermore,
consistent evidence shows that T1DM patients exhibit significantly
higher levels of circulating IL-27 [15]. Mutation of IL-27 gene in T1DM
contributes to immune disorders. Expression quantitative trait loci
(eQTL) analysis has revealed that mutations in the IL-27 gene
(rs181206) result in increased expression of interferon regulatory factor
1 (IRF-1) in CD4+T cells, promoting the production of IFN-γ in T1DM
patients [16]. In summary, the levels of circulating IL-27 exhibit oppo­
site trends during the early stages of T1DM and T2DM, suggesting its
potential as a diagnostic marker for both conditions.
Circulating levels of IL-35 also hold predictive potential in the
context of T1DM. It has been directly observed that T1DM patients with
remaining C-peptide exhibit higher levels of IL-35 [17]. The presence of
C-peptide is indicative of better functioning islet β cells, which suggests
that the severity of T1DM could be reflected by measuring circulating
levels of IL-35. Therefore, circulating IL-35 can serve as a valuable
marker for assessing the progression and severity of T1DM.
Unlike IL-27 and IL-35, the levels of IL-23 in the circulation do not
show significant variations in individuals with T1DM or T2DM [18].
However, IL-23 plays a role in local inflammation of the islets. In both
T1DM and T2DM patients, there is an increased production of IL-23 by
peripheral blood mononuclear cells (PBMCs) surrounding the islets
compared to healthy individuals [19,20]. Furthermore, an upregulation
of the IL-23 subunit, IL-23p19 (IL-23A), was observed in pancreatic is­
lets from individuals with short-duration T1DM [21]. Mutations in the
IL-23 gene have also been linked to the development of both T1DM and
T2DM [22,23]. However, there is a debate on whether circulating levels
of IL-23 also change. A study reported elevated levels of circulating
IL-23 in individuals with T2DM aged over 51 years old [18]. This finding
suggests that circulating levels of IL-23 may be associated with the
progression of diabetes. This is consistent with the findings of Eiris et al.,
who reported that genetic variations in IL-23 were linked to the severity
of T2DM [23]. Although it is not recommended to use circulating IL-23
levels as an early-stage diagnostic tool for T1DM and T2DM, it could
serve as a reference for the progression of T2DM.
It is well-known that levels of IL-12 are increased in patients with
both T1DM and T2DM [24,25]. Recent studies have focused on the
relationship between circulating levels of IL-12 and diabetic complica­
tions, particularly cardiovascular diseases. For instance, in individuals
with T2DM, higher serum levels of IL-12 have been associated with
reduced heart rate variability [26]. Similarly, T1DM patients with car­
diovascular autonomic neuropathy exhibit significantly elevated circu­
lating levels of IL-12 compared to healthy individuals [27]. Recent
research has suggested that varying levels of IL-12 can exacerbate
glucose variability, increasing the risk of diabetes complications [28].
Other members of the IL-12 family of cytokines are also closely
associated with diabetes complications. Elevated levels of IL-23 were
found to be accompanied by impaired heart rate variability [26].
Additionally, a multiplex proteomics study highlighted the close asso­
ciation between IL-27p28 protein levels and major adverse cardiovas­
cular events in T2DM [29].
J. Luo et al.
IL-12 family cytokines have the potential to not only predict and
reflect the severity of diabetes but also serve as suitable indicators for
estimating the risk of diabetes complications.
2. Roles of IL-12 family cytokines in the pathogenesis of T1DM
and T2DM
2.1. Pro-inflammatory role of IL-12 family cytokines
2.1.1. Direct effects of IL-12 family cytokines on islet β cells
The cytokines belonging to the IL-12 family have been found to
worsen inflammation by directly triggering the apoptosis of islet β cells.
This was evidenced by the activation of the Caspase-3 apoptosis marker
and the induction of dysfunction in mouse INS-1 cells (insulinoma cells
releasing insulin) when exogenous IL-12 was introduced [30]. More­
over, Radwan et al. demonstrated that inhibiting IL-12 and CHOP (an
endoplasmic reticulum stress marker) significantly enhanced the
glucose test tolerance in mice with type 2 diabetes. Since endoplasmic
reticulum stress is associated with apoptosis in islet cells, it implies that
IL-12 may activate this stress response to promote apoptosis [31].
However, there is conflicting evidence suggesting that IL-12-induced
endoplasmic reticulum stress does not directly contribute to β-cell
destruction [32]. Therefore, IL-12 may not be the primary mediator in
the process of β-cell destruction.
Although sharing the subunit with IL-12, neither IL-23 nor IL-35 was
reported directly destroy islet β cells. One possibility is that islet β cells
are more sensitive to IL-12 for the upregulation of STAT4 gene in T1DM
individuals [33]. However, IL-12 family cytokines gene has not signifi­
cantly altered in T2DM according to the islet gene map, suggesting an
indirect role on islet β cells [33].
2.1.2. Indirect effects of IL-12 family cytokines on islet β cells
The activation of IL-12 family cytokines leads to an abnormal im­
mune response that exacerbates the burden of inflammation in the
pancreatic islets. This process is influenced by the dysregulation of CD4+
T cells, CD8+ T cells, regulatory T cells (Tregs), and other cell types
(Fig. 1).
Once antigen-presenting cells (APCs) receive signals from damaged
islet cells, they transmit the signal to naive CD4+T cells. IL-12 family
cytokines play a crucial role in determining the density of CD4+T cells.
In 2002, it was discovered that IL-12 activates JAK2-STAT4, promoting
the differentiation of naive CD4+T cells (Th0) into IFN-γ producing
CD4+T cells (Th1) [34]. This activation of Th1 cells by IL-12 leads to a
positive feedback loop, as the accumulation of IFN-γ stimulates APCs to
produce more IL-12. Concretely, in the inflammatory context, IL-1β,
TNF-α,and IFN-γ collectively enhance the expression of IL-12 as pre­
sented in Weaver et al. research [35]. This perpetuates the ongoing islet
inflammation seen in T1DM and T2DM. Although IL-23 shares the same
subunit IL-12p40 with IL-12, it does not facilitate the differentiation of
Th0 cells due to the lack of IL-23R expression on Th0 cells initially [36].
However, with the help of IL-6, IL-23R is expressed, allowing IL-23 to
play a role in the differentiation and proliferation of Th17 cells [36].
Additionally, Ciecko and colleagues found that complete knockout of
the IL-27 gene in NOD mice provided complete protection against T1DM
by dampening the function of Th1 cells in the spleen, pancreatic lymph
nodes, and pancreatic islets [37].
In addition to CD4+ T cells, IL-12 family cytokines have also been
implicated in the exacerbation of CD8+ T cell toxicity in both T1DM and
T2DM progression. Dean et al., in their study, observed that the com­
bination of IL-12 and IL-18 led to increased expression of granzyme B in
CD8+ T cells [38]. The knockdown of the IL-27 or IL-27 receptor gene in
mice resulted in a weaker ability of autoreactive CD8+ T cells to pro­
liferate and activate [37]. More recently, the pro-inflammatory role of
IL-27 on CD8+ T cells has been further substantiated. CD8+ T cells
lacking IL-27 receptors exhibited a reduced capacity to differentiate into
terminal populations, namely, CD44highTCF1-CXCR6+ CD8+ T cells,
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which in turn promoted the development of T1DM [39]. However, the
mechanism behind the activation of IL-27 on CD8+ T cells remains un­
clear. In contrast, Fujimoto et al. presented evidence supporting the role
of IL-27 in suppressing the infiltration of CD8+ T cells induced by
streptozocin [40]. Above all, effect of IL-12 family cytokines on CD4+T
and CD8+T cells are mainly discussed in the pathogenesis of T1DM.
Notably, similar progress might be observed in the pathogenesis of
T2DM. This is due to the recent Mendelian randomization study that the
presence of T-lymphocyte including CD4+CD8dim and CD8+T cells
enhanced the risk of T2DM [41].
As the key regulators of immune responses, Regulatory T cells
(Tregs), known as FOXP3+T cells, play a vital role. There is a quanti­
tative decrease in circulating Tregs in T1DM patients compared to
healthy individuals [42]. This decrease is attributed to the accumulation
of IL-17, which skews the balance between Tregs and Th17 cells towards
the latter [42]. The disruption of this balance may be facilitated by the
crucial activator of Th17, IL-23. Furthermore, the functional phenotype
of Tregs is altered in the context of inflammation. They start producing
more IFN-γ and IL-17, possibly due to the cooperative action of IL-12 and
IL-18, which activated natural killing cells to compete with Tregs for
IL-2, thereby promoting phenotype alteration [38]. The decrease in
circulating levels of IL-35 is also unfavorable for maintaining the
anti-inflammatory role of Tregs [43].
Both CD4+T cells and CD8+T cells require major histocompatibility
complex (MHC) to be activated. However, Innate lymphoid cells (ILCs),
a distinct group of cells independent of specific antigen presentation,
also play a crucial role in the development of insulin resistance. This
process is closely linked to the activity of IL-12 family cytokines. For
example, when stimulated with IL-12, adipose resident ILC1s produce
increased levels of IFN-γ, which in turn leads to the polarization of M1-
type macrophages and the development of insulin resistance [44]. To
elucidate whether other members of the IL-12 family also promote
pro-inflammatory responses in ILC1s, it would be beneficial to analyze
the expression of surface receptors on these cells. In the context of
inflammation, IL-23 emerges as a significant mediator for ILC3s [45].
ILC3s contribute to adipose inflammation in the obese state by
enhancing IL-17 signaling [46]. Therefore, it is plausible that IL-23
modulates ILC3s to exacerbate inflammation associated with adipose
accumulation through the enhancement of IL-17 signaling.
2.2. Anti-inflammatory role of IL-12 family cytokines
Five members of the IL-12 family of cytokines play a role in the
immune response. Among these, IL-27 and IL-35 have been shown to
have anti-inflammatory effects (Fig. 1). At the initiation of the immune
response, IL-27 and IL-35 interact to disrupt antigen presentation. IL-27
inhibits the activity of myeloid dendritic cells (mDCs) through signaling
pathways dependent on STAT-1 and STAT-3 [47]. Studies have shown
that IL-27 released by monocytes from individuals with T1DM helps
alleviate the disease by reducing the production of pro-inflammatory
cytokines IL-17 [48]. On the other hand, IL-35 promotes polarization
of macrophages towards anti-inflammatory M2 types with higher Arg1
expression in spleen of NOD mice[49]. Both IL-27 and IL-35 are involved
in preventing inflammation in pancreatic islets and targeting various
effector T cells, including Th1, natural killer (NK), and Th17 cells [40,
43,48,50]. Additionally, IL-35, one of the most powerful negative
immunoregulatory factors in the IL-12 family, enhances the ability of
Tregs and B regulatory cells (Bregs) to produce more anti-inflammatory
cytokines, such as IL-35 and IL-10 [43,51].
As shown, IL-27 and IL-35 have distinct roles in regulating the im­
mune response, with IL-27 primarily suppressing the activity of mDCs,
while IL-35 promotes the polarization of macrophages towards an anti-
inflammatory phenotype. Together, these cytokines work to prevent
islet inflammation and exert immunoregulatory effects through their
interactions with various immune cell subsets.
As diabetes progresses, the anti-inflammatory functions of IL-27 and
J. Luo et al.
Fig. 1. The roles of IL-12 family in the pathogenesis of diabetes mellitus.
IL-35 are diminished, possibly due to the inhibition of their main sources
under inflammatory conditions [52]. The failure of activated Tregs,
which are the main producers of IL-35, to effectively suppress inflam­
mation can be partially attributed to systemic inflammation. Addition­
ally, the roles of IL-27 may vary depending on their cellular sources.
IL-27 released by activated dendritic cells (DCs) promotes inflamma­
tion [37], while that released by monocytes inhibits it [48]. This
discrepancy implies the future modulation of IL-27 for diabetes therapy.
2.3. IL-12 family cytokines in T1DM and T2DM complications
2.3.1. IL-12 family cytokines in delayed wound healing
Inflammation management and angiogenesis play crucial roles in
promoting wound healing [53]. However, patients with T2DM experi­
ence impaired wound healing due to the failure of pro-inflammatory
macrophages in the bone marrow to convert into M2
anti-inflammatory macrophages, primarily because of increased
expression of IL-12 [54] (Fig. 2). Excessive IL-12 levels contribute to an
escalated inflammatory response and inhibit collagen deposition [54].
Furthermore, the accumulation of IL-12 in the wound hampers angio­
genesis by triggering oxidative stress, promoting local inflammation,
and suppressing key angiogenic activities such as serine/threonine ki­
nase Akt activity, endothelial nitric oxide synthase (eNOS) activity, and
vascular endothelial growth factor (VEGF) signaling [55]. Conse­
quently, the elevated levels of IL-12 in T2DM patients may have detri­
mental effects on the wound healing process.
IL-23, sharing the subunit IL-12p40 with IL-12, has been shown to
delay wound healing by promoting the polarization of macrophages
towards the M1 type [56]. However, it is important to note that IL-23
may not directly stimulate macrophage M1 polarization. Instead, it
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Biomedicine & Pharmacotherapy 170 (2024) 115958
induces the polarization of macrophages into a distinct subpopulation
called M(IL-23), which differs from both M1 and M2 types. These M
(IL-23) cells selectively express IL-17A and IFN-γ. The accumulation of
IFN-γ, mediated by IL-23, further promotes the M1-type polarization of
macrophages [57].
IL-27 is known to play a role in promoting wound healing at the early
stages of the process [58]. It is produced by dermal CD301b+ DCs and
acts by activating epidermal proliferation. This activation is achieved by
increasing the expression of re-epithelialization markers, namely KRT6
and Ki67 [58]. However, in the context of diabetes, it is unclear whether
IL-27 retains its reparative capabilities. Therefore, further investigations
are needed to determine the effect of IL-27 on wound healing in diabetic
individuals.
Although there is no direct evidence about IL-35 regulation of dia­
betic wound healing, indirect evidence implies that IL-35 may be
beneficial to wound healing. Patients with diabetes suffer impaired
Tregs, which contribute to delayed wound healing [59]. Activated Tregs
are important sources of IL-35. Impaired Tregs might lead to decreased
IL-35 and ongoing inflammation. Single-cell sequencing of a diabetic
wound is needed to clarify the relationship between IL-35 and diabetic
wound healing.
2.3.2. IL-12 family cytokines in diabetic retinopathy
Th17 cells play a pathogenetic role in diabetic retinopathy. IL-12
family cytokines mainly modulate Th17 activity and indirectly partici­
pate in diabetic retinopathy.
When diabetic retinopathy (DR) develops, IL-23 triggers the release
of IL-17 by Th17 cells in the retina (Fig. 2). This interaction between IL-
23 and IL-17 contributes to the destruction of the internal blood-retinal
barrier and the tight retinal pigment epithelium [60]. However, IL-35
J. Luo et al.
Fig. 2. IL-12 family cytokines participate in the development of diabetes complications.
inhibits the production of IL-17 by suppressing the RORα and RPRγt
pathways in Th17 cells, thereby alleviating proliferative diabetic reti­
nopathy [61]. The impact of IL-27 on DR is still unclear, but some
research suggests that it may have a negative regulatory effect on Th17
function [48,62,63]. Houssen et al. found that patients with DR have
increased levels of IL-27 in their aqueous humor as a compensatory
response to inflammation [64]. This suggests that IL-27 could poten­
tially protect against DR by suppressing Th17 cells. Interestingly, while
IL-23 and IL-12 share the same subunit IL-12p40, the levels of IL-12 in
the aqueous humor have no correlation with DR [65]. This implies that
IL-23-mediated DR may primarily depend on the signaling pathway
activated by the other subunit, IL-23p19. Xu et al. supported this hy­
pothesis by demonstrating that local administration of an anti-IL23Rp19
antibody in the vitreous cavity of STZ-treated rats improved the
blood-retinal barriers [66]. Therefore, targeting anti-IL-23p19 or its
receptor may hold promise for DR therapy.
2.3.3. IL-12 family cytokines in diabetic arteriosclerosis
Macrophages play a crucial role in the development of diabetic
arteriosclerosis. The pro-inflammatory macrophages, promoted by both
IL-12 and IL-23, contribute to the worsening of arteriosclerosis [67,68].
However, IL-35 acts as a protective factor against diabetic
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Biomedicine & Pharmacotherapy 170 (2024) 115958
arteriosclerosis by indirectly inhibiting macrophage activation, pri­
marily through enhancing Tregs function [69]. The role of IL-27 in
diabetic arteriosclerosis remains contradictory. On one hand, IL-27 has
been found to improve arteriosclerosis in obese mice by inhibiting M1
macrophages [70]. On the other hand, increased levels of IL-27 have
been associated with an elevated risk of adverse cardiovascular events in
patients with both type 1 and type 2 diabetes [29,71]. Recent research
tends to support a protective role for IL-27 in arteriosclerosis, as re­
combinant IL-27 has been shown to prevent the initiation of athero­
sclerosis [72]. It is worth noting that M1 macrophages can also
upregulate the expression of IL-12, IL-23, and IL-27 [73]. Therefore, this
positive feedback loop involving macrophages and cytokines could
contribute to the development of complications in diabetes.
2.3.4. IL-12 family cytokines in diabetic neuropathy
IL-35 has been found to alleviate the neuropathic pain associated
with diabetes by increasing the proportion of anti-inflammatory M2 type
macrophages in the central nervous system, namely microglia (Fig. 2)
[57]. On the other hand, IL-23 has been shown to exacerbate cognitive
decline in individuals with diabetes by promoting the production of
IL-17 [74,75]. Additionally, reducing the levels of circulating IL-12
through the use of Resveratrol also contributes to the relief of
J. Luo et al.
neuroinflammation [76].
Intriguingly, the pathogenesis of diabetic complications does not
occur independently and may be mutually influenced. The involvement
of IL-12 family cytokines plays a crucial role in mediating these com­
plications. For instance, the development of diabetic psoriasis and dia­
betic atherosclerosis is closely linked to the IL-23/IL-17 pathway (Fig. 2)
[77]. This suggests the potential for interrupting the progression of other
diabetic complications by timely modulation of circulating IL-12 family
cytokine levels. With this perspective in mind, exploring the relationship
between diabetic retinopathy (DR) and neuropathic pain, both of which
are influenced by IL-35, becomes particularly intriguing. Additionally, it
would be worth investigating whether increased levels of IL-27 in pa­
tients with DR could potentially enhance the risks of atherosclerosis in
the future.
2.4. Interplays of IL-12 family cytokines
The pathogenesis of diabetes is not solely driven by IL-12 family
cytokines but also by their interactions with other factors. For instance,
IL-27 can activate Th cells through a STAT1-dependent pathway, lead­
ing to the upregulation of T-box expression and IL-12p35 receptor
expression. This enhances T cells’ sensitivity to IL-12 signals [78]. While
IL-23 shares the IL-12p40 subunit with IL-12, it actually suppresses the
effects of IL-12 on Th1 responses [79]. Although IL-27 can suppress the
function of Th17, it has little effect on committed Th17, which is
induced by IL-23 [62]. Furthermore, IL-35 competes with IL-12 for the
receptor IL-12Rβ2 and partially inhibits the function of IL-12 [80].
Maintaining a balance in the immune response depends on the coordi­
nation of members of the IL-12 family. Therefore, further exploration of
the interactions between the cytokines in the IL-12 family is necessary to
better understand the pathogenesis of diabetes.
3. Targeting IL-12 family cytokines for DM therapy
T1DM is currently managed through insulin therapy or even islet
transplantation during the latent stage [5]. On the other hand, the
treatment approach for T2DM involves a combination of diet therapy,
exercise, and medication. The primary objective of drug therapy is to
increase insulin levels and improve insulin sensitivity. Insulin therapy
still remains the preferred method for managing T1DM [5]. However,
long-term administration of insulin can result in complications such as
disrupted postprandial glucose absorption and an increased risk of
obesity and cardiovascular disease [81].
Insulin therapy and traditional drug therapy do not directly address
the inflammation of islets in both type 1 and type 2 diabetes. However,
timely restriction of inflammation can be beneficial in preserving the
islet β cells. The IL-12 family cytokines, which are important immune-
Fig. 3. Present and potential therapies for targeting IL-12 family cytokines.
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Biomedicine & Pharmacotherapy 170 (2024) 115958
regulatory cytokines, have shown promising potential in modulating
inflammation. Therefore, this discussion aims to provide an overview of
current and potential treatment options for T1DM and T2DM, focusing
on targeting the IL-12 family of cytokines. These treatment options
include drug therapy, combination therapy, gene therapy, cell therapy,
cytokine engineering therapy, and modulation of gut microbiota.
3.1. Drug therapy
Inhibition of IL-12 family cytokines of synthesis or signaling pathway
allows drug therapy to suppress inflammation of islets (Fig. 3).
In many cases, targeting the main sources of cytokines has proven
effective in reducing their levels. For example, by inducing autophagy in
liver macrophages, which are the primary source of IL-23, Empagliflozin
has been shown to improve non-alcoholic fatty liver disease (NAFLD)
associated with T2DM [82]. Sitagliptin, on the other hand, reduces
IL-23 production by decreasing circulating Th17 cells [19]. It is
important to note that targeting the source cells does not involve their
direct destruction, but rather disruption of the synthetic signaling
pathway. One approach to achieve this is by modifying Toll-like re­
ceptors (TLRs). For instance, Lactobacillus plantarum OLL2712 en­
hances the activity of TLR-2 and reduces IL-12 and IL-23 production
from bone marrow-derived dendritic cells [83]. Interestingly, TLR-2
inhibitors have been shown to reduce IL-27 production and alleviate
islet inflammation [84]. This discrepancy may be due to the involve­
ment of different types of TLR-2-expressing cells, suggesting that sys­
temic drug administration could potentially disrupt normal immune
responses. Additionally, other components of the signaling pathway
may hold therapeutic value. Quercetin, for example, inhibits β-catenin
in bone marrow-derived DCs, leading to a decrease in IL-12 [85].
However, it is worth noting that monocyte-derived DCs rely on β-catenin
to decrease IL-12 and limit inflammation [86]. Thus, the effect of sta­
bilizing or inhibiting β-catenin may depend on the types of DCs. Another
approach involves blocking the production of IL-12 subunits, IL-12p35
and IL-12p40, using Apilimod (STA-5326), which inhibits the migra­
tion of C-Rel (a protein involved in the NF-κB signaling pathway) from
the cytoplasm to the nucleus [87]. It is recommended that future
research investigate the effects of different pathways targeted by these
drugs on relieving inflammation in the islets.
Another potential approach is to inhibit the signaling pathway of IL-
12 family cytokines. Currently, there are two methods available for
blocking these pathways. Since IL-12 family cytokines share subunits,
drugs that bind to these subunits can hinder the activation of their
respective receptors on immune cells. Ustekinumab serves as one
example of such a drugs.
Ustekinumab, an anti-p40 monoclonal antibody approved by the
FDA for treating psoriasis, has also shown effectiveness in the treatment
J. Luo et al.
Table 1
Clinical trials of drugs for targeting IL-12 family cytokines.
Drug Target Clinical trial name
Baricitinib IL-12/ A Phase 2, Randomized, Placebo Controlled Study Investigating the
IL-23 Efficacy of Baricitinib in New Onset Type 1 Diabetes Mellitus
Ustekinumab IL-12/ Phase I/II Study of Ustekinumab in Patients With New-onset Type 1
IL-23 Diabetes
Ustekinumab IL-12/ Clinical Phase II/III Trial of Ustekinumab to Treat Type 1 Diabetes
IL-23
Lisofylline IL-12 Lisofylline as Continuous Subcutaneous and Intravenous
Administration in Subjects With Type 1 Diabetes Mellitus
Empagliflozin IL-23 Empagliflozin add-on to Insulin in Type 1 Diabetes Mellitus Over 28
Days
Sitagliptin IL-23 Effectiveness of Sitagliptin for the Treatment of Newly Diagnosed
Type 2 Diabetes
of T1DM (Table 1). Its mechanism of action involves interrupting the
downstream signaling pathway of IL-12 and IL-23 when combined with
IL-12p40. This disruption leads to a reduction in the levels of IFN-γ and
IL-6 from Th1 cells, as well as IL-17 from Th17 cells. Animal experiments
have demonstrated the feasibility of prescribing Ustekinumab for the
treatment of diabetes [88]. Furthermore, in a phase I clinical trial
(NCT02117765), Ustekinumab was found to improve inflammation in
islets of patients with T1DM when administered subcutaneously [89]. As
a result, the systematic application of Ustekinumab can be considered
relatively safe. Other drugs, such as Mirikizumab [90] and Guselkumab
[91], which antagonize IL-23p19, may also hold potential for diabetes
treatment.
In recent years, targeting the Janus kinase-signal transducers and
activators of transcription (JAK-STAT) pathway as an alternative
approach to inhibiting the IL-12 family has gained attention [12]. This is
because IL-12 family cytokines have a common characteristic of acti­
vating the JAK-STAT pathways. One JAK2 inhibitor, Baricitinib, has
been shown to inhibit Th1 differentiation through IL-12 stimulation and
Th17 differentiation through IL-23 stimulation (Table 1) [92].
Currently, Baricitinib is being tested in a clinical trial for newly-onset
T1DM patients (NCT04774224) [93]. Additionally, its therapeutic po­
tential for the treatment of T2DM should be explored, as it has the ability
to alleviate insulin resistance by reducing T-cell infiltration around
skeletal muscles and adipose tissue [94]. However, the role of other JAK
inhibitors such as Tofacitinib, Filgotinib, and Upadacitinib in the
anti-inflammatory response during the pathogenesis of T1DM or T2DM
remains unclear, as there is a lack of evidence from rodent studies.
The inhibition of phosphorylation of STAT is also being considered in
the treatment of diabetes. Lisofylline, an anti-inflammatory agent, was
first reported to be effective for Type 1 Diabetes Mellitus (T1DM) ther­
apy in 2002 (Table 1) [95]. Lisofylline works by suppressing the phos­
phorylation of STAT4, thereby inhibiting the IL-12 signaling pathway
[95]. What makes Lisofylline particularly attractive for diabetes therapy
is not only its ability to improve islet inflammation [96] but also its
potential to prevent the onset of diabetes and improve complications
[97,98]. It is possible that patients who are treated with Lisofylline at an
early stage of diabetes may be able to maintain glucose tolerance.
However, the clinical trial did not yield favorable results. The current
clinical trial (NCT06103121) was terminated due to the participant’s
illness after treatment with Lisofylline. This might be attributed to the
low specificity of Lisofylline [99]. Another drug that targets the sup­
pression of STAT4 phosphorylation is Sorafenib (Table 1). Sorafenib, an
FDA-approved antineoplastic agent, also has the potential to reduce
inflammation [100]. Although clinical trials of Sorafenib for the treat­
ment of diabetes have not been conducted, its therapeutic potential has
been evaluated. Sorafenib indirectly blocks the JAK2-STAT4 signaling
pathway of IL-12, leading to a significant decrease in Th1 cells around
islets [101]. Due to its higher specificity and lower dosage requirements,
Sorafenib is an attractive option for diabetes therapy. However, it is
important to note that Sorafenib’s immunosuppressive properties make
7
Biomedicine & Pharmacotherapy 170 (2024) 115958
patients phase Identifier www.clini
caltrials. gov/
91 participants（10–30 years old） II NCT04774224
within 100 days of diagnosis
20 adults（18–35 years old）within I/II NCT02117765
100 days of diagnosis
66 adults (18–35 years old) with II/III NCT03941132
recent-onset T1D
1 Participant (18–35 years old) with Terminated NCT01603121
T1DM
75 participants aged 18–35 years II NCT01969747
with T1DM
50 Patients with newly diagnosed IV NCT04495881
T2DM
it unsuitable for T1DM patients with infectious diseases [101]. In the
future, it is proposed to identify more specific targets for Sorafenib and
minimize its limitations.
There are several obstacles that hinder the application of drug
therapy in the treatment of T1DM. One of the main challenges is the
uncertainty surrounding the timing of drug administration. Both animal
study and clinical trial recommended that Ustekinumab should be
administered early in the course of T1DM. For instance, in NOD mice,
the injection of an IL-12p40 antagonist did not significantly delay the
onset of diabetes at 8 weeks, while the opposite effect was observed at 6
weeks [102]. Consistent with it, a phase I clinical trial (NCT02117765)
reported a significant decrease in the number of inflammatory cells in
C-peptide responders, suggesting that the drug may exhibit higher
sensitivity to islet β cells when administered in the early stages of T1DM
[89]. Also, these findings highlight the complexity of determining the
optimal timing for drug therapy in T1DM.
Additionally, there is a lack of consensus regarding the appropriate
dosage of certain drugs, such as Baricitinib, Lisofylline, and Sorafenib, as
they are dose-dependent medications. In the case of Baricitinib, a daily
dosage of 4 mg is recommended for the treatment of diabetes [93]. It has
been reported that Lisofylline at concentrations ranging from 20 to
100 mM is effective in combating islet inflammation in vitro [103]. For
the inhibition of islet inflammation in diabetes patients, particularly in
adults with latent autoimmune diabetes, a dosage of 10 mg/kg/day of
Sorafenib is proposed [101]. However, further clinical evidence is
required to establish the safe and effective dosages for these drugs.
Finally, the use of certain medications has been found to have sig­
nificant side effects that can cause concerns in various applications. For
example, the administration of Baricitinib systematically has been
observed to weaken the immune response. Similarly, taking Empagli­
flozin orally has been associated with inducing hypotension [104].
Consequently, exploring alternative administration methods for these
drugs may offer a potential solution to mitigate such side effects.
3.2. Combination therapy
Combination therapy options have been explored to further enhance
the anti-inflammatory properties of IL-12 family cytokines (Fig. 3).
Various bioactive factors have been proposed for combination with
these drugs. One potential strategy is to combine Ustekinumab with IL-2,
Treg cells, or specific adjuvants that facilitate antigen-based toleriza­
tion, aiming to preserve islet β cells [90]. Another approach involves
coadministration of Lisofylline with insulin-resistant protein (INGAP),
which has shown improved efficacy in enhancing glucose tolerance
[105]. IL-35, when combined with other immune factors, has demon­
strated promising effects in the treatment of autoimmune diseases such
as asthma and colitis [106,107]. Therefore, combining IL-35 with other
immune factors may enhance its anti-inflammatory effect on islet cells.
Of particular interest is IL-10, which can serve as a suitable partner for
IL-35. On the one hand, IL-10 exhibits immunosuppressive properties.
J. Luo et al.
On the other hand, IL-35 enhances the protective role of Tregs, given
sufficient IL-10 levels in the islets [43]. Additionally, considering the
context of inflammation, the application of IL-27 in combination with
anti-inflammatory cytokines like IL-10 and TGF-β appears to be a
reasonable approach.
In addition to incorporating assistant cytokines, an alternative
approach to address drug shortages could involve the use of modified
materials. Lisofylline, due to its high hydrophilicity and rapid metabolic
interconversion, poses challenges in maintaining its therapeutic effect
over an extended period. However, when combined with linoleic acid to
form self-assembled micelles (LSF-LA), Lisofylline exhibits a longer half-
life and improved glucose tolerance compared to the pure formulation
[99,108]. Recent studies have demonstrated that transforming LSF-LA
micelles into nanoparticulate tablets can further enhance the drug’s
half-life and bioavailability [109].
Combination therapy faces several challenges that must be overcome
for its successful implementation. Firstly, the utilization of bioactive
factors is hindered by their low concentrations and short lifespan,
making it difficult to effectively employ them in treatment. Moreover,
estimating the cost associated with modifying the delivery system for
these bioactive factors is essential, as it directly impacts the clinical
feasibility of such therapy [110]. Finally, the scarcity of clinical trials
poses a significant obstacle in establishing the safety and efficacy of
combination therapy.
3.3. Gene therapy
Gene therapy involves vaccines by modifying viral capsid proteins
and combining them with transgenic systems (Fig. 3). By engineering
capsid proteins loaded with cytokine genes, gene therapy allows for
enhanced tropism for islet β cells without triggering an antigen-antibody
response in the body [111]. Besides, gene therapy avoids administrating
the drug continuously. Hence, notable advantages of gene therapy are
the improved stability and specificity of cytokines. For example, when
an islet β cell-targeted adeno-associated virus vector with IL-35 trans­
gene (AAV8mIP-IL-35) is injected into NOD mice, only CD4+ and CD8+
T cells in the islets are reduced, resulting in decreased levels of
pro-inflammatory factors like IFN-γ and TNF-α [50]. This demonstrates
the crucial role of adeno-associated virus vectors in maintaining the
stability of exogenous IL-35. Moreover, the use of the IL-35 transgene
with an insulin promoter enhances the specificity of the islets.
Although gene therapy involving the other members of the IL-12
family of cytokines has not been previously explored for diabetes
treatment, it holds great potential. One possible approach is the use of
adeno-associated virus vectors with soluble IL-23 receptors, which has
been proved effective to protect against autoimmune encephalomyelitis
through inhibiting IL-23/Th17 signaling pathway [112]. Similarly, an
adeno-associated virus vector containing IL-27 is successful to halt the
onset of autoimmune encephalomyelitis and colitis, with the common
characteristic of inhibiting Th17 activity [113,114]. Another promising
method of gene therapy involves modifying the transcript of IL-27. For
instance, by targeting the IL-27 gene c-terminus with IL-27pL, the
effectiveness of glucocorticoids in improving the treatment of rheuma­
toid arthritis was enhanced [115]. This is attributed to the peptide’s
specific binding to the interleukin 6 receptor type 1 (IL-6Rα), which is
also involved in the inflammatory response observed in diabetic islets
[90]. Altogether, gene therapy of IL-12 family cytokines are applicable
for harmonizing the immune disorders, which is hopeful for diabetes
therapy.
3.4. Cell therapy
Cell therapy refers to the enhancement of immunoregulation through
either modifying cells or adopting cellular immunotherapy (Fig. 3). One
approach to cell modification involves transfecting cells with modified
cytokine genes. For example, mesenchymal stem cells (MSCs) modified
8
Biomedicine & Pharmacotherapy 170 (2024) 115958
with the IL-35 gene (IL-35-MSCs) have been successful in inhibiting
CD4+T cell proliferation and increasing the proportion of Tregs [116]. In
animal models of autoimmune hepatitis and ulcerative colitis,
IL-35-MSCs have demonstrated efficacy, indicating their potential for
the treatment of Type 1 Diabetes Mellitus (T1DM) [116]. Another
avenue for cell modification under consideration is the modification of
DCs to tolerant phenotypes. Spleen DC cells transfected with the
single-chain IL-35Ig fusion gene have shown promising effects in
reducing pro-inflammatory immune cells surrounding islet β cells [117].
Similarly, modifying bone marrow-derived DCs to overexpress autoim­
mune regulators (AIRE) can decrease IL-27 production, which impedes
the secretion of islet-specific antibodies [118]. However, it is important
to carefully select the type of DCs for cell modification, as increased
expression of IL-27 from myeloid DCs can induce the tolerant phenotype
of DCs [47]. Adoptive cellular immunotherapy involves extracting
anti-inflammatory immune cells surrounding the islet and proliferating
them in vitro. These proliferated cells, along with additional factors such
as IL-2, IL-10, and IL-35, are then implanted into the body to combat
inflammation. Chimeric antigen receptor Tregs (CAR-T) therapy is an
example of adoptive cellular immunotherapy [119]. CAR-T has advan­
tages in enhancing specificity towards islets independently of MHC and
increasing the ratio of Tregs/Teffs [119]. However, a single infusion
only delays the development of T1DM instead of preventing it entirely
[120]. To address this, the addition of a low dose of IL-2 is proposed in
CAR-T therapy to enhance the function of Tregs [121]. Likewise,
IL-35-producing regulatory B cells (Bregs) also play a crucial role in
maintaining immune balance. Bregs directly induce the intolerance of
DCs, indirectly inhibiting the activation of pathogenic CD8+T cells
[122]. Further research is needed to determine whether it is possible to
design CAR-B cells with additional IL-35 to improve diabetes.
3.5. Cytokines engineering therapy
To optimize efficiency, it is advantageous to manipulate cytokines
and their receptors (Fig. 3). Cytokine engineering holds great promise as
it enables to modify the signaling pathways of IL-23 by modulating IL-23
receptors (IL-23R). When cytokines bind to receptors, it triggers a
conformational rearrangement, which in turn activates downstream
signaling pathways. An interesting finding reported that the deletion of
the extended stalk regions of IL-23R prevented IL-23-mediated confor­
mational rearrangement while maintaining the activation status in cells
[123]. This technique, known as receptor interface engineering, inspired
us to explore the possibility of specifically controlling signaling and
restraining the activity of target cells by modifying the receptor. If
successfully applied to diabetes patients, this could protect pancreatic
islets from inflammation without adversely affecting the immune
system.
Recently, researchers have developed Supercytokines to address the
limitations of natural cytokines. One approach to fabricating Super­
cytokines is the synthesis of cytokines called Synthekines, which are not
found in nature. These Synthekines are created by fusing two subunits
from different cytokines to activate distinct signaling cascades [124].
Promising results have been obtained in animal experiments investi­
gating the therapeutic potential of Synthekines for diabetes treatment.
Specifically, a fusion of two subunits from the IL-12 family cytokines,
IL-12p40 and IL-12p28, called scIL-Y, demonstrated effectiveness in
preventing the onset of diabetes in NOD mice [125]. Overall, further
research could explore the fusion of subunits from other IL-12 family
cytokines, such as IL-12p28 and IL-12p35, to expand the range of ap­
plications for Supercytokines [125].
3.6. Gut microbiota modulation
Recent research has highlighted the strong correlation between gut
microbiota disorder and the development of both T1DM and T2DM
[126,127]. One significant link between gut microbiota and diabetes is
J. Luo et al.
the role of IL-12 family cytokines, which serve as crucial intermediaries
(Fig. 3). In NOD mice lacking gut microbiota, higher levels of IL-12 were
observed, accompanied by elevated autoantibody titers [128]. More­
over, the dysbiosis of gut microbiota contributes to the disruption of the
intestinal barrier through the release of IL-12 family cytokines.
Maintaining the integrity of the intestinal barrier is crucial in
combating systemic inflammation and reducing the risk of obesity-
related conditions. One way to achieve this is by reducing IL-23 and
increasing IL-27 levels, as these cytokines contribute to intestinal barrier
integrity [129,130]. For instance, the probiotic Clostridium Faecali­
bacterium prausnitzii has been found to stimulate IL-27 secretion by
dendritic cells and promote IL-10 production by regulatory T cells,
effectively enhancing the body’s anti-inflammatory response. This
finding has potential implications for reducing inflammation in the islets
[131].
Surprisingly, even if the intestinal barrier is disrupted, the body has
another mechanism to resist obesity. Intestinal bacteria produce a
metabolite that induces intestinal B cells to secrete IL-35, especially
under high-fat diet conditions. This secretion of IL-35 helps suppress
inflammation and prevents the development of type 2 diabetes [132].
When targeting IL-12 family cytokines through manipulation of the gut
microbiota, it is crucial to consider the order of treatment [133]. In
healthy individuals, maintaining intestinal homeostasis relies on the
early involvement of CD4+ T cells and the later maintenance of innate
lymphoid cells (ILCs). Therefore, it is suggested that in the initial stages,
establishing a gut microbiota profile related to IL-12 can enhance the
role of CD4+ T cells. Subsequently, establishing a gut microbiota profile
related to IL-27 and IL-35 can further enhance ILC stability and function.
4. Conclusion
Diabetes is the chronic disease largely associated with immune dis­
orders. Here, we highlight the strong relationship between IL-12 family
cytokines and diabetes by analyzing the changing rules of IL-12 family
cytokines. Further, we investigate the roles of IL-12 family cytokines in
T1DM and T2DM. The imbalance of pro- and anti-inflammation in islet β
cells is attributed to the disordered regulation of IL-12 family cytokines.
We provide the new insights to investigate the functions of IL-12 family
cytokines in diabetes and complications from the view of compositions.
Novelly, IL-12 family cytokines serve as the bridges between metabolism
and immune disorders by modulating ILCs. As for the role of anti-
inflammation, the inhibitory effects of IL-27 and IL-35 reflects on
almost every step of innate response, including antigen-presentation,
effector cells activation, and inhibitory cytokines releasing. Also, IL-12
family cytokines play a crucial role in diabetes complications
including delayed wound healing, retinopathy, arteriosclerosis, and
neuropathy. It implies that targeting IL-12 family cytokines not only has
the advantages of relieving islet inflammation, but also improves dia­
betes complications. Hence, targeting IL-12 family cytokines possess
tremendous potentials for diabetes therapy.
We introduce present and potentials strategies, including drug
therapy, combination therapy, gene therapy, cell therapy, cytokines
engineering therapy, and gut microbiota modulation. Drug therapy re­
lieves diabetes through hindering the synthesis and disrupting the
signaling pathways. However, issues like medication safety (e.g., timing,
dosage, and toxicity) require further investigation. Combination therapy
complements the effect of cytokine targeting by supplementing bioac­
tive factors and modifying delivery systems. Unfortunately, the efficacy
of bioactive factors and the costs associated with optimizing delivery
systems hinder widespread application. Gene therapy raises the speci­
ficity and stability of cytokines. But related research was only conducted
in animals. Cell therapy, cytokines engineering therapy and gut micro­
biota modulation have an attractive effect on enhanced specificity and
controlling inflammation, becoming momentum for further study. It is
crucial to explore various strategies for targeting IL-12 family cytokines
that are safe, effective, accessible, cost-effective, and capable of
9
Biomedicine & Pharmacotherapy 170 (2024) 115958
maintaining stability. This will pave the way for improved treatment of
T1DM and T2DM. Further research are needed to overcome the existing
challenges and advance the field of targeting IL-12 family cytokine for
diabetes therapy.
Funding
This work was supported by National Natural Science Foundation of
China [Grant/Award Numbers: 81970930].
CRediT authorship contribution statement
Jiayu Luo: Conceptualization, Investigation, Writing – original
draft. Tingting Ning: Conceptualization, Data curation. Xing Li: Formal
analysis, Resources. Tao Jiang: Formal analysis. Shenglong Tan:
Visualization. Dandan Ma: Funding acquisition, Project administration,
Supervision, Writing – review & editing.
Declaration of generative AI and AI-assisted technologies in the
writing process
During the preparation of this work, the author(s) used Wordtune in
order to improve language. After using this tool, the author(s) reviewed
and edited the content as needed and take(s) full responsibility for the
content of the publication.
Declaration of Competing Interest
We declare that we have no financial and personal relationships with
other people or organizations that can inappropriately influence our
work, there is no professional or other personal interest of any nature or
kind in any product, service and/ or company that could be constructed
as influencing the position presented in, or the review of, the manuscript
entitled.
Acknowledgments
This work was supported by the National Natural Science Foundation
of China Grants (No. 81970930). We thank the Southern Medical Uni­
versity of China for language support. Figures in the review were created
with Biorender.com.
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