Critical ReviewsTM in Immunology, 39(4):239 – 265 (2019)

Pathophysiology, Etiology, Epidemiology of Type

1 Diabetes and Computational Approaches for
Immune Targets and Therapy
Begum Dariya,a Gayathri Chalikonda,b Gowru Srivani,a Afroz Alam,a &
Ganji Purnachandra Nagarajub,*
a
Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India;
b
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322,
USA
*Address all correspondence to: Ganji Purnachandra Nagaraju, PhD, DSc, FAACC, Department of Hematology and Medical Oncology, Winship
Cancer Institute C#3025, Emory University, Atlanta, GA-30322, USA; Tel.: +1-470-585-8202, E-mail:pganji@emory.edu

ABSTRACT: Autoimmune diseases occur when the body’s natural defense system fails to differentiate its own cells
from the foreign cells and mistakenly attacks the healthy cells. Among the autoimmune diseases, the most common
serious disease is the type 1 diabetes (T1D). Biomarkers like c-peptide, autoantibodies, and glycated molecules are
now widely used for the early diagnosis of diabetes. However, the diverse nature of biomarkers and the available au-
toantibodies as biomarkers are not enough to differentiate the heterogeneity inherent in T1D. Novel biomarkers have
allowed the introduction of bioinformatics for assimilating the new data into clinical tools. Computer-aided drug design
contributes to the discovery of novel autoantibodies, and molecular docking promises to enhance it. Moreover, the study
of the pathophysiology of diabetes via molecular simulation has been proposed. In this review article, we focus on the
characterization of the etiology, epidemiological factors, and mechanisms of hyperglycemia that induce cellular damage
due to oxidative stress and proinflammatory responses. We also decribe novel biomarkers used for the detection of β-cell
destruction and diagnosis at early stages. Bioinformatics tools including molecular docking, sequence alignment, and
homology modeling are also presented. This report supports researchers in drug design, in disease detection at an early
phase, and in therapy development for T1D-associated complications.

KEY WORDS: type 1 diabetes, etiology, epidemiology, biomarkers, β-cells, insulin, hyperglycemia, complications,
bioinformatics, docking

ABBREVIATIONS: 2D DIGE, two-dimensional difference gel electrophoresis; AGE, advanced glycation end products; APC,
antigen-presenting cells; AR, aldose reductase; bdnf, brain-derived neutrophic factor; CD4, cluster of differentiation; DAG, diacyl
glycerol; DAN, diabetic autonomic neuropathy; DPN, diabetic peripheral neuropathy; ECM, extracellular matrix; ESI, electro-
spray ionization; esRAGE, endogenous secretion RAGE; GAD, glutamic acid decarboxylase; GFAT, glutamine:fructose-6-phos-
phate amidotranferase; GLUT, glucose transporter; GPPAD, global platform for the prevention of autoimmune diabetes; HbA1c,
glycated hemoglobin; HLA, human leukocyte antigen; IA-2, insulinoma 2–associated autoantibody; IAA, insulin autoantibod-
ies; ICA, islet cell cytoplasmic autoantibody; IFN, interferon; iNOS, inducible nitric oxide synthase; JM, juxta-transmembrane;
LC-MS, liquid chromatography-mass spectrometry; MA, microalbuminuria; MALDI, matrix-associated laser desorption ion-
ization; MHC, major histocompatibility complex; MNP, mononuclear phagocytic cells; NF-κB, nuclear factor kappa B; NIH,
National Institutes of Health; PBPP, platelet-based protein precursor; PDGFR, platelet-derived growth factor; PKC, protein ki-
nase C; PLN, pancreatic lymph node; PTMs, posttranslational modifications; PTP, protein tyrosine phosphatase; SDH, sorbitol
dehydrogenase; Shc, Src2 homology domain containing; SUR, sulfonylurea receptor; T1D, type 1 diabetes; TGF-β1, transcription
growth factor beta 1; TOF, time of flight; TNF, tumor necrosis factor; URP-GlcNAc, uridine diphosphate N-acetylglucosamine;
VEGF, vascular endothelial growth factor; ZNT8A, zinc transporter 8 autoantibody

I. INTRODUCTION distinguish its own cells from invaders, it attacks it-

The healthy immune system functions to shield the
body from any harmful foreign substances, includ-
ing parasites, bacteria, and cancer cells. However, if
the immune system behaves abnormally and fails to
self with autoantibodies. Thus, any individual with
an autoimmune condition has an elevated risk of de-
veloping excessive inflammation and tissue damage,
which are hallmarks of autoimmune disorders. To
date, researchers have identified > 80 autoimmune

1040-8401/19/$35.00 © 2019 by Begell House, Inc. www.begellhouse.com239

240 Dariya et al.
disorders, and the National Institutes of Health
(NIH) estimates that ~ 23.5 million individuals in the
United States are affected by such diseases. Autoim-
mune disorders can be categorized into two types,
namely a systemic autoimmune disease that attacks
many organs and a localized one that attacks a single
organ. The diagnosis of an autoimmune disease is dif-
ficult and misleading because these diseases change
in severity over time. Common symptoms include
fatigue, rash, dizziness, and joint pain. Autoimmune
disease has no cure but needs therapy only to ease
the symptoms. The most common autoimmune dis-
orders are type 1 diabetes (T1D), multiple sclerosis,
rheumatoid arthritis, celiac disease and Alzheimer’s
disease. In this report, we have focused on T1D.
T1D, insulin-dependent diabetes mellitus, is a
disorder in which the body cannot produce enough
insulin. This chronic disease is mediated by type IV
hypersensitivity, a cell-mediated immune response
driven by aberrant T lymphocytes that recognize pan-
creatic islets of Langerhans, damage insulin-making
β cells, and cause disease progression.1,2 This ge-
netic aberration causes the loss of self-recognition in
the T cells and targets β-cell antigens. Furthermore,
these T cells recruit other CD4+ and CD8+ T cells to
target β cells. The common symptoms experienced
by patients are polyphagia, glycosuria, polyuria, and
polydipsia. Hyperglycemia and deficiency in insu-
lin are the prime reason for 5%–10% of diagnosed
diabetes cases. T1D is the most prevalent disease,
with the incidence mostly in the population under 18
years of age worldwide, with higher rates in Finland
and Sardinia and lower rates in China and Venezu-
ela.3 Additionally, the international research DIA-
MOND and EURODIAB reported the highest graph
peak for T1D occurs in the youngest population.3
Moreover, an increase in the incidence rate among
children was reported globally to be ~ 3%–5% every
year since 1960, mostly in developing countries.4–8
The exact cause for the disease is not understood;
environmental conditions, autoimmunity, and ge-
netic factors are all9 believed to play critical roles
in the disease onset. T1D is characterized by the
dysregulation of glucose, which if untreated can
be fatal.10 Although there is no way to completely
prevent T1D, 1993 publications from the landmark
diabetes control and complication trial reported that
the disease can be treated with the adoption of in-
tensive insulin therapy.11 Furthermore, pancreatic
transplantation or β-cell regeneration can restore
organ function. On the other hand, managing these
complications is the crucial goal of the clinical and
research fields, that is, to save a patient’s life. A clear
knowledge of the structure of the proteins, their in-
teractions, and detection of biomarkers for early di-
agnosis are essential.
Bioinformatics serves as an interdisciplinary
model for molecular biology and computational
sciences. It includes interconnected databanks of
clinical data. Additionally, computational tools and
algorithms are used to determine similarity, homol-
ogy sequencing, and envisioning the 3D structures
of a protein along with the amino acid sequencing.
Thus, determining the interaction of a drug and a
protein becomes much easier with bioinformatics.
In this review article, we have focused on the epi-
demiology, signaling pathways, and complications
caused by T1D with an in silico approach.
II. EPIDEMIOLOGY AND ETIOLOGY
A. Epidemiology
The symptomatic and presymptomatic natures of
the disease can be estimated for the analysis of ep-
idemiology. The International Diabetes Federation
estimates that 8.8% of adults worldwide have dia-
betes. Interestingly, T1D is much less prevalent than
T2D; T1D is commonly diagnosed in children aged
< 15 years, with > 500,000 children affected cur-
rently and 900,000 new diagnoses every year.12 Oc-
casionally, this disease is diagnosed after 50 years
of age,13 as evidenced by a genetic risk score from
the UK Biobank which states that the adult onset is
42% for those aged 31–60 years.14 It is mostly fre-
quently diagnosed in developed countries like Eu-
ropean countries, Australia, and North America and
less so in countries like Japan, China, and South Ko-
rea. These epidemiological variations may be due to
the genetic susceptibility associated with the class
II HLA (human leukocyte antigens) haplotypes (but
non-HLA loci are also reported to be susceptible),
environmental, and/or lifestyle factors. The geno-
type HLA-DR-DQ always varies among countries,
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy241
and European people with this genotype are at
higher risk than those with an Asian background.15
Additionally, the risk is also high in children of im-
migration parents.16 According to the studies from
the UK Prospective Diabetes, younger adults diag-
nosed with T2D are also consistent phenotypically
with T1D because they have β cells that target auto-
antibodies.17 When the incidence rates between gen-
ders were compared, girls had a higher peak than
boys.18,19 However, the incidence rate increases with
age; the incidence gradually decreases in women
but continues to be high for men.3 Environment and
lifestyle are interlinked and are accompanied by ad-
vances in the economy and industry, and they play
a key role in the pathogenesis of childhood T1D.20
Additionally, the nutritional factors and microbial
infections are also risk factors for developing an au-
toimmune disease.21
In another aspect, presymptomatic T1D is
considered a hallmark for epidemiology, and its
autoantibodies act as biomarkers. The identifi-
cation of these markers is an obstacle due to the
heterogeneity in T1D in children. This heterogene-
ity includes autoantibodies against glutamic acid
decarboxylase (GAD) and insulin autoantibodies
(IAA), which promote the disease by initiating an
autoimmune process at different ages.22–25 Stage 2
symptomatic progression of T1D is always diag-
nosed after the detection of multiple autoantibod-
ies, whereas the initial antibodies can be diagnosed
only at the seroconversion age of the patient. For
instance, for stage 3 symptomatic T1D, according
to TEDDY’s study,26 those under 5 years of age de-
tected with 1, 2, and 3 autoantibodies showed in-
cidence rates of 11%, 36%, and 47%, respectively.
According to the DAISY, BABYDIAB, DIPP, and
BABYDIET analyses, the multiple autoantibod-
ies targeting islets in 585 children of ages 5, 10,
and 15 years with higher risk for incidence were ~
44%, 70%, and 84%, respectively.26 In adults, the
prevalence of the detection of IAA decreased with
increasing age; prevalences of 0.8% and 1.1% for
GAD65 in adults were detected in two studies.27,28
The progression of the autoantibodies was deter-
mined only within 2–4 years of age.26,28,29 Thus, this
could be characterized for developing preventive
measures for the therapy.
Volume 39, Issue 4, 2019
B. Etiology
The etiology factors for the autoimmunity targeted
against islet cells include autoantibodies, genetic,
and environmental factors. The autoantibodies are
first screened in infants with a T1D father or mother,
allowing the targeting of the genetic and environ-
mental factors.29
1. Autoantibodies
As reported, β-cell destruction by the antibodies
starts at an early stage, and ~ 90% of the cells are
destroyed before the symptomatic stage. These au-
toantibodies attack insulin and GAD65 starting at
> 1 year of age. Moreover, the incidence for the
insulin antibodies is highest in patients with the
HLA-DR4-DQ8 haplotype and HLA-DR3-DQ2
for GAD65.29 In addition, other antibodies are lo-
cated in the secretory vesicles that attack tyrosine
phosphatase molecules: IA-2, IA-2β, and ZNT8.
Although the functions of IA-2 and IA-2β are not
known, ZNT8 reportedly passes Zn ions from the
cytoplasm to the secretory vesicles.29 The risk of
these antibodies is illustrated in Table 1.
2. Genetics
T1D is a polygenically inherited disease. Although
the HLA genes are important for the immune re-
sponse, other groups of genes, located on chromo-
some 6 that code for the major histocompatibility
complex (MHC),33–35 help recognize foreign cells
and maintain self-tolerance. The loci that play a key
role in developing autoimmunity are HLA-DR and
HLA-DQ, with their alleles HLA-DQB1, HLA-
DRB1, and HLA-DQA1. Moreover, the grouping
of haplotypes DR3-DQ2 and DR4-DQ8 are cor-
related with a higher risk of the disease.36 Addition-
ally, the non-loci HLA cells also contribute to >
50% of the risk for T1D according to genome-wide
association studies.37 Nevertheless, other genes are
involved in the growth and progression of autoan-
tibodies in stages 1 and 2, respectively. Such genes
include INS, IL2RA, IFIH1, and CTSH, among oth-
ers (Table 2).
242 Dariya et al.
TABLE 1: Etiology: autoantibodies
Autoantibodies
GAD65
Insulin
Protein phosphatase molecules
Autoantibodies
IA-2 and IA-2β
ZNT8 (3 variants having Trp, Arg, Gln at
position 325)
TABLE 2: Genes involved in progression of autoantibodies
Protein Gene
Proinsulin-insulin INS
Erb-b2 receptor tyrosine kinase 3 ERBB3
Protein tyrosine phosphatase, nonreceptor PTPN22
type 22
Protein tyrosine phosphatase, nonreceptor PTPN2
type 2
IL-2 receptor subunit α IL2RA
3. Environment
Environmental factors include diet as well as re-
gional toxicity differences. Diet takes into account
breast feeding in infancy, diversity among diets,
including gluten, cow milk, rye, egg, as well as vi-
tamins in foods. Other factors include gestational
infections, viral infections, and the gut microbiota.
The chemical toxins include nitrites, nitrates, N-ni-
troso compounds, and polychlorinated biphenyls,
which damage β cells through immunological path-
ways. Due to such environmental factors, the epi-
genetic modifications promote autoimmunity.
4. Epigenetics
Epigenetics is a term used to define what is beyond
genetics, and it acts as a mediator for environmen-
tal risk factors. As such, these changes are stable
and alter heredity due to changes in the chromatin
without DNA sequence changes. Common epigen-
etic modifications include miRNA regulation, DNA
Age Genetic haplotype Ref.
>1 HLA-DR3-DQ2 30
1-2 HLA-DR4-DQ8 30
Risk
Reaching stage 3 31
Stage 1 and stage 2 32
Dysregulated function of the gene Phase
Low expression of thymus and Stage I and II
tolerant against proinsulin
Regulates β-cell apoptosis Stage I and II
Expressed due to the activation of T Stage I and II
and B cell antigen receptor
Sensitive to the induction of β-cell Stage II
apoptosis
Respond to IL-2 present in T cells
—
and T memory cells
methylation, and histone modification. DNA meth-
ylation is the most commonly detected risk factor
associated with the secretion of insulin in the body.
Various studies have indicated that variation in
methylation is seen at the 4 CpG site of the tran-
scription site of the insulin gene in T1D patients. The
methylation of DNA has been observed at CpG-34,
CpG-135, CpG-19, and CpG-180. These genetic al-
terations near the pre-proinsulin coding sequences
increase the risk of T1D development.38 Similarly,
for histone modifications, acetylation is increased in
the lys 9 of the H3 histone protein (H3K9Ac) in the
susceptible HLA-DRB1 and HLA-DQB1 in T1D in-
dividuals.39 Also, epigenetic modifications in miRNA
result in alterations in the immune response, cell cycle,
and apoptosis. As reported in studies about miRNA
expression in the regulatory T cells of T1D patients,
a few miRNAs (including miRNA 31, miRNA-100,
miRNA-125b, miRNA-365, miRNA-335, miRNA-
20b, miRNA-99a and miRNA-151) are underex-
pressed and miRNA-146a is overexpressed. These
gene expressions indicate that miRNAs are also
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy243
associated with the regulation of immunity.40 Thus, a
clear understanding of the association of epigenetics
and environmental risk factors for the occurrence of
T1D is essential for the moderation of the disease.
III. BIOMARKERS
Abnormality in the pathology of any disease is
predicted for the onset of the disease by indicators
called biomarkers, which play a vital role in the di-
agnosis and prognosis in the clinical field. Various
biomarkers have been developed for the detection,
prevention, and therapy of a disease, such as the
DAISY, DIPP, DIPIS and TEDDY screenings, with
biological samples based on age, sex, geography,
and risk factors. For instance, the most common
biomarkers are serum diagnostic markers that de-
tect hyperglycemia, C-peptide, and autoantibodies.
These biomarkers involve monitoring glycated he-
moglobin (HbA1c) for the recent history of blood
sugar levels. Furthermore, hyperglycemia condition
causes far-reaching oxidative and inflammatory ef-
fects. Recently, a serum profile of 19 prediabetic
patients from the birth to the onset of disease was
prepared by Moulder et al.41 to narrow down markers
for predicting the progression of the disease. Previ-
ously, a change in the levels of chemokines and cy-
tokines expressions was detected in children at high
risk for T1D.42,43 Moreover, the increased expres-
sion of IL-16, IL-18, IL-6, and TNFα has been ob-
served in T1D children.44 Purohit et al.45 later noted
the downregulation of 4 cytokines (IL-8, MCP-1,
MIP-Iβ and IL-Ira) in serum samples of T1D pa-
tients. The C-peptide and insulin are released in
equimolar concentrations from the vesicles packed
as proinsulin.46 C-peptide levels, which are sensitive
to β-cells, play a crucial role in differentiating T1D
from T2D.47 Additionally, predictive biomarkers are
essential for detecting the silent asymptomatic de-
struction period of β cells. Autoantibodies are the
primary markers for diagnosis and prediction of
T1D. The autoantibodies produced in response to
autoantigens include insulin autoantibody (IAA),
glutamic acid decarboxylase (GADA), islet-cell
cytoplasmic autoantibody (ICA), zinc transporter
8 autoantibody (ZNT8A), and insulinoma-2 associ-
ated autoantibody (IA-2). These autoantibodies are
Volume 39, Issue 4, 2019
mostly screened in patients with a first-degree rel-
ative having an HLA genotype for T1D diagnosis.
In addition, the appearance, epitope, number, and
affinity of autoantibodies are even correlated with
the risk of T1D.48 For instance, GADA and IAA are
most frequently screened in children as the first au-
toantibodies, yet they disappear with age at clinical
onset.26,49–52 Furthermore, the seroconversion-linked
susceptibility loci (including PTPN22, INS, SH2B3,
and ERBB3) are reported as the higher-risk geno-
types, whereas the ERBB3 and SH2B3 are specifi-
cally connected with the autoantibody appearance.53
Post-translation modifications and splicing of β-cell
proteins are caused by the endoplasmic reticulum
and β-cell oxidative stress triggered by inflamma-
tion. The post-translational modifications reported
in T1D are citrullination of endoplasmic reticulum
chaperon’s glucose-regulated protein 78,54 type II
ROS modified collagen,55 phosphorylation of pe-
ripherin,56 and oxidative insulin.57 Nucleic acids are
also employed as biomarkers because they carry ge-
netic and epigenetic changes associated with disease
development and progression. Among them, DNA
methylation is a biomarker for the diagnosis of dis-
ease. The presence or circulation of amylin DNA
and unmethylated insulin showing no methylation at
the CpG sites of the insulin gene in β cells have been
detected in the bloodstream and have been explored
as markers for the destruction of β cells, which is an
early sign of disease onset.58 MiRNAs also play a
key role in regulating the pathogenesis of T1D and
β-cell function; thus, they represent potential bio-
markers. Approximately 200 miRNAs have been
observed in murine and human samples with T1D.59
Previous studies have reported upregulation in the
expression of miRNAs detected in the serum samples
of T1D: miRNA-24,60–62 miRNA-21,60,61,63 miRNA-
210-5p,61,63 miRNA-181a-5p,61,64 miRNA-148a.60,61
An increase in the circulation of miRNA-375 has
been correlated with the destruction of β cells in
T1D patients.60 Other miRNAs have been found
in the serum as well, including miRNA-21 and
miRNA-210.63 Although miRNA-21a, miRNA-93,
and miR-146 are typically downregulated, miRNA-
326 expression is increased in T1D.65–67 Also, me-
tabolomics biomarkers have been studied for their
use in diagnosis; lipids, metabolites, and small
244 Dariya et al.
molecules have been evaluated. Amino acids (me-
thionine)68 and lipid metabolites (sphingolipids,69
phospholipids70) have also been explored for their
biomarker utility. Further advances that contribute
for the prediction and progression of the disease are
needed to improve T1D detection and monitoring.
IV. PHYSIOLOGY OF β-CELLS PRODUCING
INSULIN
The pancreas is a heterocrine organ of the digestive
and endocrine systems that performs both exocrine
and endocrine functions. The endocrine functions
depend on the microscopic cluster of cells called is-
lets of Langerhans, which constitute 1%–3% of the
complete pancreatic mass. The islets in the pancreas
are in turn divided into four cell types: glucagon-se-
creting α cells, insulin producing β-cells, somatosta-
tin producing δ-cells, and polypeptide-producing
cells.71 Among these, the major source of insulin
production is pancreatic β cells.71–73 The β cells
sense the glucose circulation in the blood, which
stimulates insulin and concomitantly releases it.71
The glucose enters the pancreatic β cells through
GLUT (GLUT1 in humans and GLUT2 in rodents)
membrane-bound glucose transporters. Once in the
β cells, the glucose undergoes phosphorylation via
glucokinase and hexokinase, which further pro-
duces ATP by glycolysis. Moreover, the ratio of
glucokinase and hexokinase also determines the
glucose sensed by β cells. The gradual increase of
ATPs in the β cells causes the KATP channel closure,
membrane depolarization, and opening of the volt-
age-gated calcium channels. The rapid influx of Ca2+
and subsequent increased intracellular Ca2+ lead to
the development of vesicles filled with insulin that
attach to the membrane and release via exocytosis.
V. SYNTHESIS OF INSULIN
Insulin is an anabolic hormone that maintains glu-
cose homeostasis. It functions to carry and transport
glucose to various tissues for energy metabolism.
Skeletal muscles and adipocytes comprise most
glucose consumption. Its synthesis is similar to that
of other peptide hormones and begins with the for-
mation of linear polypeptide pre-proinsulin, which
is cotranslationally inserted into the endoplasmic
reticulum lumen. The small peptide fragment pres-
ent at the N-terminal signal sequence region is re-
moved by the signal peptidase to form proinsulin.
The proinsulin then transits from the endoplasmic
reticulum to the Golgi apparatus (cisternae), where
it forms disulphide bonds between the A and B
chains and is packaged into clatherin-coated ves-
icles containing insulin and C-peptide (i.e., con-
necting peptide). Later, inside the vesicle, insulin
and the C-peptide are separated and then exocy-
tosed into the cytoplasm from the β cells in equi-
molar concentrations. Thus, the C-peptide acts as
a marker for insulin secretion during T1D diag-
nosis.74 The active insulin initiates its pathway by
binding to the membrane receptor proteins at the
α subunit on the outside the cell and activates it.
Later, the β subunit attached to the α subunit to-
ward the inner side becomes autophosphorylated,
which further activates a local tyrosine kinase and
eventually phosphorylates varied number of multi-
ple intracellular enzymes including insulin recep-
tor substrates. This process stimulates the glucose
transport channels, GLUT, on the cell surface, which
allows cells to take in glucose and store it for future
use.
VI. PATHOPHYSIOLOGY: THE IMMUNE CELL
TRAFFICKING AND β-CELL APOPTOSIS
In T1D, the insulin-producing pancreatic β cells are
reduced by 70%–80% due to insulitis and necrosis
of the tissue. This process eventually causes loss of
function over years. This pathology is due to the au-
toimmune destruction mediated by the autoantibod-
ies released against the islet cell antigens.75,76 The
T cells are present inside the islets of Langerhans,
causing destruction of the insulin-producing β cells.
Along with the T cells, macrophages, and mediators
(including oxygen free radicals, cytokines, and nitric
oxides) are all involved in insulitis. Earlier, Hostens
et al.77 determined that the β cells, when exposed to
IL-1β and IFN-γ, show similar functional changes
as in prediabetic patients. Later, Ohara et al.78 also
determined that IL-1β also mediates decrease in the
docking of insulin vesicles to the β cell membrane,
thereby resulting in the prevention of the first phase
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy245
of insulin secretion. Further introduction of β cells
to TNF-α, IL-1β, and IFN-γ eventually causes β-cell
death.79
Immune cell trafficking during T1D progression
initially starts with T cells that escape the negative
selection in the thymus and make their way toward
the pancreatic lymph node (PLN) to traffic into the
islets. On the other side, the antigen-presenting cells
(APCs) produce β-cell antigen to target PLN in a
pathological manner.80–82 The activated T cells in the
PLN later infiltrate the islets via extravasation af-
ter recirculating within the thoracic, lymphatic duct,
and bloodstream. These further recruit additional
lymphocytes into the islets.83 Additionally, the T
cells are stimulated repeatedly with their interaction
with the APCs present on the CD11c+, resulting in
the production of cytokines, like IFN-γ. The specific
pancreatic T-cell response is detected during the on-
set of T1D due to MHC II rather than MHC I through
the islet antigens produced by dendritic cells. Thus,
an inflammation environment with an increased
number of B cells and mononuclear phagocytic cells
(MNP) is created due the IFN-γ production, which
further upregulates the production of chemokines
and vascular adhesion molecules in the endothelia
of the islets.81,84,85 The CD11c+ cells behave as gate-
keeper cells that recruit both T and B cells to the
infiltrated islet cells.86 In addition, the CD11c+ also
produce ~ 20 different chemokines with the ability
to bind to the receptors on islet T cells.86 Further-
more, the initial islet-targeting autoantibodies pro-
duced reflect the autoantigens from the dendritic
cells, CD4+ and CD8+ T cells, in the islet.
These processes result in the insufficient release
of insulin, eventually causing glucose overproduc-
tion and, thus, the descreased intake of glucose by
the cells, resulting in hyperglycemia. Additionally,
the loss of insulin also causes the breakdown of fats
and the oxidation of fatty acids, resulting in ketone
overproduction and diabetic ketoacidosis.87–89
The pathophysiology results from autoimmune
destruction and nonautoimmune destruction of the
islet cells. As discussed earlier, the genetic com-
ponents that play a crucial role are HLADR3 and
HLADR4. Moreover, the parents with heterozygos-
ity of these genes are at advanced risk for the oc-
currence of the disease. Additionally, PTPNN2, the
Volume 39, Issue 4, 2019
promoter of insulin, also impairs islet cells. Later,
the autoimmune response includes islet cell autoan-
tibodies (ICA) and anti-GAD65 antibodies, which
further contribute to autoimmune diseases. The
Cocksackie B virus is also involved in the progres-
sion of T1D through molecular mimicry. The fol-
lowing subsections describe the factors that promote
T1D.
A. Autoantibodies
The islet autoantibodies are fundamentally rec-
ognized as the markers for T1D, and their respec-
tive antigens present on the secretory granules in
the β cells, including the zinc transporter ZnT8-
(ZnT8A),90 insulin-(IAA),91 GAD65-(GADA)92 and
the protein tyrosine phosphatase-like protein IA-2-
(IA-2A).93 Autoantibodies also recognize the ho-
mologous isoforms IA-2β94 and GAD67.95
1. GAD65-GADA
GAD65 is an enzyme that exists in the multiprotein
complex of the cytoplasmic side membrane of the
synaptic like microvesicle. The structure includes 3
domains, a terminal NH2 domain, a middle domain
with a proximal 5’-phosphate (PLP) cofactor bind-
ing site, and a terminal COOH catalytic domain.96,97
It plays a central role in catalyzing the biosynthesis
of GABA. GABA is a gamma aminobutyric acid
that is the inhibitory of the neurotransmitter in the
central nervous system (CNS). Additionally, they
also exist in adult human pancreatic islets, more so
in β cells than in α cells.98 The GAD67, an isoform
of GAD65 shows almost 76% homology with it.
Moreover, the GAD67 was detected to be expressed
in the epithelial cells of thymic medulla that act as
self-antigens and are capable of escaping from the
auto reactive lymphocytes.99 GADA is characterized
as such, it recognizes the epitopes present on the
antigen in T1D. GAD65 can be divided into three
different categories: GADA engaged against NH2
terminal domain epitope, GADA engaged toward
the middle PLP binding domain site, and GADA to
the COOH terminal domain epitope.100,101 The fre-
quency of positivity of the autoantibodies during the
onset of disease is > 80%.102
246 Dariya et al.
2. Insulin IA-2 -IA-2A
The insulinoma associated antigen is like an intrinsic
protein present at the membrane of secretory granules
and is a receptor-like protein tyrosine phosphatase
(PTP). In the pancreas, it is present in the α, β, and
γ cells of the islets.103 Structurally, the ectodomain
promotes the localization into the lumen of secretory
granules, the cytoplasmic single juxta-transmem-
brane (JM), and a PTP-like cytoplasmic domain.
During the mechanism of Ca++ promoting insulin se-
cretion in the pancreas islets, the cytoplasmic domain
of IA-2 is cleaved to promote the secretory granule
mobilization toward the plasma membrane.104 Addi-
tionally, the cleaved IA-2 further migrates toward the
nucleus, which promotes the expression of genes re-
sponsible for the secretory granules functions, includ-
ing insulin secretion and expansion of β cells.105 Thus,
IA-2 and heterodimers with IA-2β interact with the
other diverse proteins for functioning of the β-cells
in the islets of the pancreas for insulin secretion. The
expression of IA-2 at the mRNA and protein levels
has been detected in the splenocytes and thymus
and it escapes the negative selection in the thymus
of self-reactive immune cells.106 The IA-2A/antibody
acts in two ways during the onset of disease: it is di-
rected toward the epitope of cytoplasmic JM domain
or it is directed toward the epitope in the PTP-like
domain.107,108 The frequency of the presence of IA-2A
at the onset of T1D is > 70%.102
3. ZnT8-ZnT8A
The zinc transporter ZnT8 protein is a transmem-
brane multi mass protein that has 6 transmembrane
domains and a loop rich in histidine inserted between
the IV and V domains.109 It forms a homodimer, in-
serted into the secretory granule membrane, where
its histidine rich loop inserts towards the lumen and
the NH2/COOH terminal domains into the cyto-
plasm. The expression of ZnT8 at its mRNA level
is confined only for the islets of the pancreas110 with
its increased expression detected in β-cells than in
α-cells.111,112 Functionally, it maintains the Zn con-
tent in the cells and is critical to get collected into the
secretary granules. Additionally, it also maintains
the insulin tightly packed as hexamers. The epitopes
for the ZnT8A are present at the NH2 and COOH ter-
minal domains90; moreover, ZnT8-positive patients
are detected with 10% of the NH2 domain epitope
and many with the COOH domain epitope during
diagnosis. The frequency for the positive existence
of ZnT8A is > 65%.102
4. Insulin Antibodies/IAA
The association between the autoreactive lympho-
cytes and the polymorphic variants of the insulin
gene are at the higher genetic risk for T1D. IAA
binds with the conformational epitopes; however,
they do not interact with the reduced antigen. More-
over, the binding of IAA occurs with high affinity
with the A chain of insulin at the 8–13 amino acid
residues and with a low affinity with the B chain
at the 28–30 amino acid residues. The frequency
of the positive occurrence of this autoantibody
at the onset of T1D is > 50% compared to other
autoantibodies.102
5. HLA
The human leukocyte antigen, HLA, weighs ~ 4,000
kb and is positioned on the 6p21.3 human chromo-
some. It functions via immune response to the envi-
ronmental factors in various autoimmune diseases.113
HLA antigens comprise 2 classes: HLA class I that
encodes the genes (A, B, C) and HLA class II mole-
cules that encode for the genes (DP, DQ, DR). Most
are associated with autoantibodies. However, inter-
action with autoantibodies is strong only with the
HLA class II loci in T1D, which contributes a risk of
~ 40%–50%.114,115 GADA has been detected to bind
with more affinity with the HLA DR3-DQ2 haplo-
type, whereas IA-2A and IAA are more strongly cor-
related with HLA DR3-DQ8.116 HLA class I and class
II antigens present on cells that are recognized by
the CD8+ and CD4+ T lymphocytic cells, respectively.
However, a stronger risk is detected with the HLA
class II for the onset of T1D.117 The non-HLA–as-
sociated antigens that include susceptible genes for
T1D are INS, PTPN2, CTLA4, PTPN22, IFIHI, and
CLEC161. Approximately 50 non-HLA gene loci
have been determined as genetic risks for the onset of
T1D according to a genome-wide association study.
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy247
The allele scores and nucleotide polymorphisms of
non-HLA indicate the stratified risks for the develop-
ment of islet autoantibodies that form the basis of the
progression to symptomatic T1D.118 Thus, both HLA
and non-HLA indicate a genetic risk ~ 10- to 100-fold
higher in individuals who have relatives with T1D.
Additionally, monozygotic twins have also been re-
ported to have a 65%–70% higher risk of developing
T1D at an early age.10 Moreover, siblings that share
the HLA haplotypes DR3-DQ2/DR4-DQ8 are at 12-
fold higher risk for developing asymptomatic disease
within 15 years if one sibling was already diagnosed
with disease before 10 years of age.119
VII. STAGES OF T1D
The rate of progression starting from the stage of on-
set of β-cell autoimmunity until the onset of glucose
intolerance and then to the symptomatic T1D lasts
from few months to decades in children or adults. It
can be differentiated into stages basing on the clin-
ical symptoms including the metabolic imbalance
and hyperglycemia. Currently, T1D is classified ac-
cording to its prognostic significance.
A. Stage 1
The individuals in stage 1 are screened with at
least 2 islet autoantibodies including IA-2, ZnT8,
GAD65 and insulin; however, they have normogly-
cemia. The children, if screened for genetic risk at
birth and if they reach stage 1, are at risk for disease
at age 5 or 10 years, with a frequency of 44% and
70%, respectively, and they have a 100% lifetime
risk.26 PTPN22 and INS expressions can be detected
in the development of stage 1 T1DM.120 Moreover,
the immune stimuli encountered in the childhood
influence the development of stage 1 T1D. The de-
velopment from stage 1 to stage 2 is detected via
the oral glucose tolerance test (OGTT)121,122 for the
presence of dysglycemia as well as an increase in
the levels of HbA1c.123
B. Stage 2
Individuals with stage 2 are screened for more than
two autoantibodies, like stage 1; however, they
Volume 39, Issue 4, 2019
show increased glucose intolerance due to β-cell
dysfunction and loss. The 5-year risk for this symp-
tomatic stage is ~ 75% and 100% for lifetime risk.124
The rate of progression in this stage is higher due
to the influence of T1DM susceptible genes, but the
biomarkers for diagnosis at this stage are still lack-
ing. The non-HLAs are extensively encouraged as
biomarkers for detection during stage 1; however,
the gene for non-HLAs that contribute to pathogen-
esis in the stages 2 and 3 have yet to be investigated.
Additionally, the ZNT8 autoantibody variants in-
clude tryptophan, glutamine, and arginine at the 325
amino acid position.32 Moreover, stage 2 dysglyce-
mia exists for more than a year before the onset of
symptoms in stage 3 T1D.
C. Stage 3
At this stage, the signs of diabetes and clinical symp-
toms appear, including weight loss, fatigue, poly-
uria, ketoacidosis, and polydipsia. With the onset of
stage 3, the autoimmunity targeted against β cells
is increased and prolonged. The occurrence of the
IA-2 autoantibody increases the risk for reaching the
stage 3 from stage 2.31 The data from the fine-needle
biopsy shows the occurrence of CD4+, CD8+, den-
dritic cells, macrophages, T cells, and B cells in the
pancreatic islets of Langerhans.125,126 According to
estimates from the DAISY, BABYDIAD, DIPP, and
BABYDIET, children showed higher risks of 44%,
70%, and 84% at 5, 10, and 15 years, respectively.26
In addition, the TEDDY studies determined that the
seroconversions at 5 years were 11%, 36%, and 47%
for 1, 2, and 3 autoantibodies, respectively.127
VIII. CLINICAL SYMPTOMS OF T1D
The primary clinical symptoms of T1D include
polydipsia, polyuria, and weight loss, and ~ 90%
of the T1D patients present with these common
symptoms. Polyuria, weight loss, excess thirst, and
hunger are hyperglycemia-associated symptoms.
When the blood glucose level is > 180, it surpasses
the renal threshold, leading to osmotic diuresis and
polyuria. Polyuria is excess urination due to the high
levels of sugar present in the blood. The urine in the
kidneys is reabsorbed due to the glucose present and
248 Dariya et al.
is further directed into the bloodstream. However, in
T1D, the kidneys lose the function of reabsorbing
glucose and it ends up in the urine. Similarly, poly-
dipsia is excessive thirst accompanied by prolonged
and temporary dryness of the mouth and prolonged
dehydration causing headache, nausea, dizziness,
and fainting. If not diagnosed, this pathology further
leads to ketoacidosis, which further causes organ
failure, coma, and death. Ketoacidosis is a result of
lipid breakdown to ketone byproducts to substitute
for glucose88; it also causes fruity breath. The other
symptoms include hyperphagia, visual disturbances
due to retinal defect, perianal candidiasis, and yeast
infection.
IX. COMPLICATIONS OF T1D
The complications of T1D are differentiated as
microvascular and macrovascular. Microvascular
complications include neuropathy, nephropathy, and
retinopathy, whereas macrovascular complications
includes peripheral vascular, cardiovascular, and
cerebrovascular diseases.
A. Microvascular Disease
The serious disabling complication for T1D is reti-
nopathy, which affects adults aged 20–74 years.128 It
develops in 4 stages: Microaneurysms develop due
to balloon-like swelling in minute blood vessels of
the retina, causing blockage of the blood vessels and
depriving them from the supply of blood. To com-
pensate the blood vessels, the retina starts develop-
ing new blood vessels, but this can lead to blindness
because the retina has thin fragile walls and blood
may leak.128,129 In addition, cataracts and glaucoma
are also frequently diagnosed in diabetic patients.128
Nephropathy is another complication of T1D
that develops secondary to metabolic abnormali-
ties.130,131 According to clinical analysis, it is diag-
nosed with increased albumin secretion in the urine
(30–299 mg/24 h). Thus, the renal end-stage results
with the progression from microalbuminuria to
macroalbuminuria. Additionally, it is also associated
with increased risk for cardiovascular disease and
death. Thus, this may be a useful marker for cardio-
vascular risk.132,133
Neuropathy is a neuropathic abnormality that
includes diverse clinical complications and a het-
erogeneous group of disorders like diabetic periph-
eral neuropathy (DPN) and autonomic neuropathy
(DAN).130 The risk factors for DPN include hyper-
glycemia, duration of diabetes, lipid levels, and
blood pressure; for DAN, the duration of diabetes,
age, and uncontrolled glycemic levels are critical
factors.134 DPN is asymptomatic but contributes to a
higher risk of foot infection and amputation.134
B. Macrovascular Disease
Macrovascular complications are less well studied
than the microvascular. However, coronary artery
disease is the most common risk factor that varies by
sex.135 Additionally, severity in retinopathy, higher
body mass index, and blood pressure, proteinuria,
and depression are risk factors for cardiovascular
disease.136 Atherosclerosis is abundantly caused by
cardiovascular disease due to plaque development
in the arterial walls that impairs blood flow. Further-
more, a deeper understanding of the mechanism in-
volved that potentiates the clinical interventions for
the prevention of diabetic complications is essential.
X. SIGNALING PATHWAYS INVOLVED IN PRE
AND POST T1D
The pathogenesis in T1D is generally related to the
aberrant behavior of various signaling pathways in-
cluding the insulin, AMPK, and PPAR pathways.
The signaling pathways play crucial roles in novel
drug targeting and therapies for diabetes.
A. Insulin Signaling Pathway
As discussed, earlier insulin maintains glucose ho-
meostasis and is facilitated by the binding of insulin
to its receptors called insulin receptors. The receptor
is a tetrameric glycoprotein with 2 extracellular α
and 2 intracellular β subunits.137 The insulin binding
to the α subunit leads to autophosphorylation and
activation of the β subunit, further phosphorylating
various intracellular substrates including IRS1-4
(insulin receptor substrate) and Shc (Src 2 homol-
ogy domain containing). Further, IRS activates
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy249
PI3K serving as a docking site for the subunit p85 of
PI3-K. The activated PI3K further phosphorylates
PIP2 to PIP3. Also, the PTEN pathway regulates the
function of IRS and PIP3 by inhibiting its expression
whenever required. The increased concentration of
PIP3 recruits PDK (phosphoinositide-dependent
protein kinase), protein kinase C, and Akt (protein
kinase B) toward the plasma membrane. The acti-
vated PDK phosphorylates Akt at threonine 308.
Because Akt requires serine for phosphorylation,
the mTORC2 complex phosphorylates Akt at ser-
ine 473. Thus, the activated Akt promotes glycogen,
protein, and lipid syntheses.138,139 Moreover, the ves-
icles in the cells embedded with GLUT4 are trans-
located to the plasma membrane; they play a crucial
role in glucose uptake. Therefore, the AS160 protein
activated by Akt translocates GLUT4 to embed it
into the plasma membrane. Akt also follows another
cascade in the activation of GSK3β that promotes
glycogen synthesis and axon growth. Alternatively,
the autophosphorylated β subunit also phosphory-
lates Shc, which attracts Grb-2 and recruits the GTP
exchange factors SOS and GTP protein Ras. The
activated Ras further follows a series of steps for
MAPK activation, thus promoting the expression of
genes, mitogenesis, and cell progression.138,140 How-
ever, in T1D patients, the lack of insulin disturbs its
downstream signaling via dysregulation of the PI3K
pathway. The IRS protein plays a crucial role in the
insulin-signaling pathway. Although it is normally
phosphorylated at the serine to inhibit the insulin
signaling pathway, in T1D it acts abnormally and
remains overphosphorylated at the serine residue to
promote degradation via the ubiquitin-proteasome–
mediated pathway. This process results in the im-
paired signaling cascade of insulin.
B. Mechanism of β-Cell Apoptosis
Autoimmune attacks result in an inflammatory reac-
tion called insulitis in T1D. In this process pancreatic
β cells target various immune cells including T cells
and macrophages, causing invasion of mononuclear
cells in the islets of the pancreas. The attack results
in the loss of β-cell mass in the advanced stages of
T1D. β-cell apoptosis is the most crucial part of the
T1D; it has been observed to cause depletion of β
Volume 39, Issue 4, 2019
cells in rodents.79 The expression of various inflam-
matory mediators including cytokines targets a com-
mon cascade of apoptosis, later loss of β-cell mass,
and finally diabetes.141,142 Thus, apoptosis of the β
cells is activated by various phosphorylation cas-
cades, activated extracellular signals, and irregular
expression of anti- and proapoptotic genes and intra-
cellular ATP levels.79 An extensive microarray analy-
sis of the expression of genes during the exposure of
β-cells to cytokines IFN-γ and IL-1β revealed ~ 700
genes that are downregulated or upregulated in their
expressions.143–146 For instance, IL-1β in mice or in
human islet cells was upregulated, whereas NF-κB
expression was downregulated. Exposure of β cells
to IL-1β led to loss of insulin secretion as well as a
decline in the migration and docking of insulin gran-
ules to the membrane of β-cells. Moreover, exposure
for longer periods to IFN-γ, IL-1β, and TNF, results
in β-cell apoptosis.79 In general, the cytokines act by
promoting stress-response genes that either protect
or damage the survival of β cells. The transcription
factor NF-кB is activated by IL-1β and is inhibited
by the super-repressor IкB, which protects β cells
against cytokine-mediated apoptosis. Additionally,
NF-кB regulates the expression of iNOS and other
transcription factors, including PDX-1 and Isl-1,
that are involved in the progression of β cells via
NO production. Thus, the endoplasmic reticulum
Ca2+ homeostasis, progression, and apoptosis of β
cells are directly or indirectly regulated by IL-1β–
dependent NF-кB activation. Moreover, IFN-γ in
support of IL-1β was determined to be involved in
the apoptosis of β-cells, wherein IFN-γ activates the
JAK tyrosine kinase that further phosphorylates the
STAT-1 transcription factor, which translocates into
the nucleus and binds at diverse γ-active genes.79
Thus, STAT potentiates IFN-γ on iNOS-mediated
IL-1β expression.147 In support of this finding,
Cnopet al.148 also determined that mice deficient in
STAT-1 showed no damage in β cells because they
are protected against IL-1β and IFN-γ. Thus, it is
evident that IL-1β, along other inflammatory modu-
lators like IFN-γ or TNF-α, showed increased JNK
activity and aberrant STAT-1 expression. In addi-
tion, p38 MAPK targets ER homeostasis, and death
signals from the mitochondria also induced β-cell
apoptosis.149–151 P53, the tumor suppressor protein
250 Dariya et al.
that lies downstream to NO-dependent MAPK acti-
vation, is also upregulated.152 The dysregulated en-
doplasmic reticulum Ca2+ concentration disturbs ER
homeostasis and promotes ER stress. The prolonged
stress results in the upregulation of ER chaperons
JNK, MAPK and caspase-12, which that further
promotes apoptosis.153 The mitochondria not only
regulate the function and survival of β cells but also
promote apoptosis.154,155 The apoptotic functionality
of the mitochondria is mediated by the Bcl-2 fam-
ily, which regulates the release of cytochrome c into
the cytosol and subsequently activates caspase 3 and
caspase 9 to promote cell death.156 Thus, the fate of β
cells depends on the duration and severity of expo-
sure to cytokines and the network of genes activated
by them, which finally cause β-cell apoptosis and
eventually T1D.
C. The Mechanism of Signaling Pathways
in T1D Associated with Hyperglycemia
Untreated or undetected T1D results in higher con-
centrations of intracellular glucose levels, clinically
called as hyperglycemia. This condition is reported
with excessive oxidative stress, production of ROS,
and tissue damage. These effects cause breaks in
DNA strands, activating PARP, which results in the
release of ADP ribose polymers that alter GAPDH
activation through polymers docking with them.
This process eventually narrows glycolysis and di-
rects the glycolytic intermediates toward pathogenic
signaling pathways including the formation of ad-
vanced glycation end products (AGEs) in intracel-
lular, higher flux of polyol pathway, hyperactivation
of hexoamine pathway and PKC pathway. This pro-
cess causes cellular stress, leading to micro- and
macrovascular complications. Thus, hyperglycemia
weakens glycolysis and causes glycolytic intermedi-
ates to accumulate, which deactivates the enzymes
prostacyclin and NO synthase.
D. Advanced Glycosylation End Products
(AGE)-RAGE (Receptor) Pathway
A high blood glucose concentration results in the
formation of irreversible nonenzymatic glycation
products: advanced glycation end products (AGEs).
These AGEs are formed with an oxidation reaction
between carbonyl groups of sugar and amine groups
of proteins. The intermediates thereby include non-
stable Schiff bases (lysine/arginine) and covalently
bound amadori products (ketoamine). Moreover,
reports indicate that AGE products cause diabetic
complications.157 In addition to the interaction of
intra- and extracellular protein, AGEs also interact
with their receptors, the central cell-surface recep-
tors RAGE.158 The binding of the ligand with the re-
ceptor activates proinflammatory cytokines, which
promotes inflammation and oxidative stress. Thus,
under a hyperglycemic condition, RAGE expression
is upregulated due to the increased availability of
AGE products and the ablation of the RAGE gene,
Ager, which reduces insulin resistance. Thus, target-
ing RAGE could be a therapeutic strategy for T1D
therapy and treatment of related complications. The
interaction of AGE and RAGE also induces various
signaling pathways downstream, including MAPK/
ERK, PKC, JAK/PI3K, and Src. Additionally, this
interaction activates NF-кB, which transcribes
genes engaged in inflammation, and similarly Egr1,
which transcribes genes for adhesion and cell mo-
tility. Thus, intracellular AGE production aberrantly
activates various signaling pathways and transcrip-
tion factors, which that ultimately results in diabetic
complications. Moreover, as discussed earlier along
with the development of insulin resistance, AGEs
also cause β-cell dysfunction and increased ROS
production, which impairs mitochondrial function.
The T1D complications include kidney hypertrophy
as well as increase in the glomerular filtration rate
due to the lower secretion of endogenous secretory
RAGE (esRAGE) and secretory RAGE (sRAGE).159
Thus, an inverse relationship occurs between the
concentration of endogenous secretion RAGE and
kidney volume function; increased levels impair the
vascular complications of diabetes.160 Similarly, dia-
betic retinopathy subsequently causes blindness due
to blood vessel formation on the retina. McVicar et
al.161 determined that diabetic Ager (AGER gene)-
null mice showed lower retinal capillary degrada-
tion, adherent leukocytes in the retina, and decreases
in F4/80+ microglia. Additionally, an increase in
glyoxalase-1, which regulates the activity of meth-
ylglyoxal, is a precursor for the engagement of
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy251
RAGE and AGE compared with wild-type diabetic
mice. In another study, Han et al.162 determined that
brain-derived neutrophic factor (BDNF) plays a
crucial role in amending neuroplasticity and that its
overexpression in the hippocampus impairs hyper-
glycemic-induced neuroinflammation by blocking
NF-кB and RAGE pathways. Thus, blocking the ex-
pression of RAGE and availability of AGE products
could reduce diabetes-related complications.
E. Polyol Pathway
The polyol pathway is aldose-reductase (AR) de-
pendent and plays a crucial role in complications
including oxidative stress, nephropathy, cardio-
myopathy, and platelet hyperaggregation.163 It is a
dual-step process that includes the conversion of
hexose sugar (glucose) into polyol, a sugar alco-
hol. First, glucose is converted into sorbitol in the
presence of the AR enzyme. The rate-limiting en-
zyme and NADPH cofactor are further oxidized into
fructose in the presence of sorbitol dehydrogenase
(SDH) with NAD+ as a cofactor. The fructose is then
converted into advanced glycosylation end products
(AGE) that include fructose-3-phosphate and 3-de-
oxyglucosone.163 In the general process, glucose
metabolization is carried out via the hexokinase
pathway; however, due to the hyperglycemic condi-
tion, glucose levels saturate the hexokinase pathway
and become metabolized through the polyol path-
way. Thus, 30% of glucose is metabolized through
this pathway and only 3% of aldohexose is altered
into sorbital under normoglycemic conditions. Ad-
ditionally, the polyol pathway also induces oxida-
tive stress by decreasing the availability of NADPH
for glutathione reductase to maintain a glutathione
pool because glutathione is used vigorously by AR
as a cofactor. Moreover, SDH activity also pro-
motes the production of superoxide anion because
it increases the concentration of NADH, a substrate
for NADH-dependent oxidase and AGE produc-
tion, which subsequently enhances ROS production.
Thus, the development of the oxidation stress via
the polyol pathway is the entire source for glucose
flux, which causes various complications including
neuronal degeneration, retinopathy, and neovascu-
larisation. Furthermore, Liu et al.164 determined that
Volume 39, Issue 4, 2019
the genetic removal of the Ar gene in diabetic mice
inhibited PKC and TGF-β1 activities, which play a
major role in accruing extracellular matrix and glo-
merulosclerosis. The use of inhibitor for AR also at-
tenuates ERK and Akt activity in renal cells, which
may be a novel strategy for diabetic nephropathy
prevention.165 Moreover, Marko et al.166 determined
that the early occurrence of cataracts in the pediatric
patients of T1D in their first stage was due to oxi-
dative stress, the polyol pathway, and the osmotic
pathways. Recently, Akamine et al.167 described the
complications associated with T1D and T2D on the
basis of circadian properties. In both cases, diabetic
neuropathic pain is due to the accumulation of sor-
bital in the peripheral nervous system, which results
in dysregulation or inhibition of Na+/K+-ATPase
activity, which results in diabetic neuropathic pain.
However, this pain is circadian dependent in T2D
and not in T1D. Thus, proper knowledge of circa-
dian properties of the symptoms and their under-
lying mechanisms will support the development of
more effective therapies.
F. Hexosamine Pathway
Excess intracellular glucose (~ 2%–5%) is also
pushed into another pathogenic pathway called the
hexosamine pathway, which ultimately contributes
to diabetes-related macrovascular disease. The path-
way includes fructose-6-phosphate as a substrate
obtained from glycolysis and glutamine, which are
further converted into glucosamine-6-phosphate
and glutamate, respectively, in the presence of glu-
tamine: fructose-6-phosphate amidotransferase
(GFAT) enzyme. Glucosamine-6-phosphate is then
metabolized into uridine diphosphate N-acetylglu-
cosamine (UDP-GlcNAc).168,169 UDP-GlcNAc acts
as a substrate for the O-GlcNAc transferase in gly-
cosylation, and it is involved in the addition of a sin-
gle sugar to proteins, which causes posttranslational
protein modifications at serine or threonine residues.
This phosphorylation of the protein regulates the
function of various enzymes, transcription factors,
and proteins that alter various cellular processes.
The hexosamine signaling pathway enhances O-Glc-
NAcylation, which stimulates the expression of var-
ious transcription factors including transforming
252 Dariya et al.
growth factor (TGF-β1) and plasminogen activator
inhibitor (PAI-1). This process causes pathogenic
tissue damage in diabetic patients.170 Additionally, it
also targets VEGF-A in retinal cells, which causes
vascular lesions in diabetic retinopathy.171 However,
the inhibition of GFAT downregulates the expres-
sion of TGF-β1172 and PAI-1169 and increases O-Glc-
NAcylation, which causes diabetic complications.173
Thus, this process contributes to pathophysiological
abnormalities in T1D, and an in-depth exploration
of these mechanisms may yield novel therapeutic
strategies for the therapy of T1D.
G. Protein Kinase C (PKC) Pathway
Intercellular hyperglycemia results from the activa-
tion of the PKC pathway, and it is associated with
diabetic complications. PKC belongs to the phos-
pholipid-dependent serine/threonine kinase family,
which plays a crucial role in cell progression, sur-
vival, glucose, and lipid metabolism. PKC has three
isoform groups: α, βI/II, and γ. The hyperglycemic
condition enhances the expression of diacylglycerol
(DAG), which activates the PKC pathway in the
heart (PKC-βII), kidneys, and glomeruli (PKC-βI),
leading to various vascular complications. DAG is
the cofactor obtained from the products of glycol-
ysis, including glyceraldehyde-3-phosphate and di-
hydroxy-acetone phosphate. In addition, activated
PKC under a hyperglycemic condition induces di-
abetic pathogenesis, contributing to the progression
of extracellular matrix, angiogenesis, and alteration
in vascular permeability.174 Among the isoforms,
PKC-β is the major cause of pathogenesis in dia-
betes, and it also promotes ECM (type IV collagen
and fibronectin) proliferation and the expression of
TGF-β protein.175 However, ECM accretion and the
expression of TGDF-β have been reported to be de-
layed when exposed to PKC inhibitor. Furthermore,
NADPH oxidation and impaired ROS production
are absent in PKC-β null mice; thus, PKC-β also
induces oxidative stress through the oxidation of
NADPH.176 Similarly, PKC-γ, along with p38α and
MAPK, promote Src homology-2, which causes
apoptosis independent of NF-кB activation and de-
phosphorylating PDGFR β. In addition, PKC also
induces endothelial cell permeability in diabetes,177
which further contributes to oxidative stress and
lowers NO bioavailability.168,178 Furthermore, hy-
perglycemic conditions also induce reproductive
dysfunctions in males with T1D; the involved meta-
bolic pathways are the PKC, polyol, and AGE recep-
tor pathways. Activated PKC and polyol pathways
have been detected within both in the testis and the
epididymis. Moreover, AGE activates CDC42 and
Akt1 to cause dysfunction in the reproductive sys-
tem.179 All of these discoveries provide opportuni-
ties for the development of therapies for diabetic
complications.
XI. UNDERSTANDING THE BIOLOGY AND
INTERACTIONS OF PROTEINS IN T1D
THROUGH BIOINFORMATICS
Bioinformatics is a field of interdisciplinary research
of computer sciences and information technology
applied together in the fields of research and med-
icine. It deals with biological databases that play a
central role in understanding the biological phenom-
ena and the interactions among various macromole-
cules. Additionally, bioinformatics analyses unravel
the genetic basis of various metabolic diseases, like
diabetes mellitus, to target after the completion of
the human genome project. Proteomics techniques
are now being widely explored for a clearer under-
standing of T1D progression. Biomarkers are being
characterized for therapeutic purposes because they
are specific, sensitive, and readily available in small
samples. Proteomic researchers are now focusing
on mapping the proteomes associated with the pan-
creas and β cells,180 including the identification of a
whole protein or the peptide obtained after protein
digestion. This process is initiated by determining
the mass to charge ratios and then searching for the
protein in database. Ionization is also performed
prior to the mass analysis using electrospray ion-
ization (ESI) and matrix-associated laser desorp-
tion ionization (MALDI). These techniques use a
time of flight (TOF) instrument. Merchant et al.181
performed LC-MALDI-TOF, a tandem mass spec-
trometry shotgun proteomics analysis, to determine
high-molecular-weight kininogens. Isolated samples
from the Joslin study of the natural history of micro-
albuminuria (MA) in the plasma peptidome of T1D
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy253
patients showed matching cystatin C eGFR and MA
with patients with early progressive renal function
decline, and with subsequent follow-up for 8–12
years. They reported three fragments of high-molec-
ular-weight kininogen and a peptide des-Arg9-BK
(1-8) that promotes the expression of Erk1/2 phos-
phorylation. Thus, this fragment was identified as a
protein correlated with early progressive renal func-
tion decline in T1D patients with MA. Although MA
is recorded as a diagnostic tool for the detection of
T1D,182 the association of MA with the future risk
of renal function is always a question because most
MA patients reverted back to urine free of albu-
min,183 and only 20% of the patients showed protein-
uria,184 and TID patients showed early progressive
renal dysfunction.185 Thus, this technique has po-
tential to determine the protein for the cause of dis-
ease. Crevecoeur et al.186 combined microarray with
2D-DIGE for identifying the islet in 3-week-old di-
abetic NOD mice. They suggested that the islet pro-
tein showed posttranslational modifications (PTMs)
in the presence of peptidyl arginine deiminase 2.
Moreover, the 2D-DIGE proteome also determined
that NIT-1 β cells are much prone to ER and ox-
idation stress than αTC-1 cells.187 Later, Zhang et
al.188 compared the proteomic profile of the acinar
tissues with that of human islets using nano LC-MS.
They profiled 706 and 1,104 proteins, respectively.
Later, they compared LCM islets and islets isolated
in the presence of enzymes and showed overlapping
proteomic profiles. A detailed study of T1D-associ-
ated biomarkers is a significant tool for the clinical
management of T1D. As discussed earlier, the de-
tection of islet antigen cells, including GAD, IA-2
and S1c30A8 (Zn protein), could be a biomarker for
the initiation of autoimmunity in β cells.90,189 The en-
vironmental determinants of diabetes in young con-
sortium and DASP remain undefined because not all
of the antibodies involved in T1D progression and
pathogenesis have been determined.190
In another way, the prototyping of diseases like
diabetes is being used to validate bioinformatics. The
researchers have used the discovery of biomarkers
as the basis to detect disease. Initially, they found
genes that are highly associated with the occurrence
of diabetes. Later, they identified other factors re-
lated to the causes of the disease using microarrays
Volume 39, Issue 4, 2019
and t-tests to generate data and compare them be-
tween patients with T1D and autoantibody-positive
individuals. Then, univariate statistical analysis is
performed between these populations. Transcript
mapping is another technique that includes the use
of an algorithm to determine the Hamilton path to
connect genes with the proteins they encode.191 A
6-Mb map of chromosome 20, which is linked with
diabetes, has been designed for use in developing
novel targeted therapies.192
The most important database available for T1D
is the TIDbase (http://T1DBase.org).193 It comprises
data from various resources, such as BLAT and Beta
Cell Gene Bank, and includes various software tools
such as T1Dmart, Gbrowse, and Cytoscape. The
Jackson Laboratory Type 1 Diabetes Mouse Re-
pository (http://www.jax.org/resources/index.html)
is another important resource. This nonprofit orga-
nization contributes to medical research and their
database includes data about genetics, biology, and
genomics.
The major techniques used to extract the pro-
teomic data include microarray and mass spectrome-
try; however, because these techniques are manually
performed, they are time-consuming. Thus, re-
searchers have collaborated with mathematics and
computer sciences to improve the analysis of protein
data. Molecular docking is the bioinformatics tool
used to predict the interaction between a drug and a
ligand before in vitro and in vivo studies. Thus, this
field plays a major role in drug design. Presently, a
large amount of research on ligand–protein docking
is being conducted to design drugs to treat diabe-
tes mellitus. For instance, foot ulcers are a major
complication for both T1D and T2D. As an initial
step, a clinico-bioinformatics analysis is performed
for both male and female diabetic patients with foot
ulcers.194 Male diabetic patients are highly prone to
morality because a foot infected with MDR-GNB
shows a more irregular glycemic secretion rate in
men than in women. Additionally, the interaction
sites for the ligand and protein are Asn132, Pro167,
Lys234, Glu166, Val172, and Thr235 of enzyme
CTX-M-15 and the drug cefotaxime, which has an
enzyme drug complex.195 Homology modeling is the
prediction of the structure of any protein due to its
similarity with more than one protein sequence of
254 Dariya et al.
known or unknown structures.196,197 The commonly
used homology modeling techniques are the SWISS-
MODEL (http://swissmodel.expasy.org/) and MOD-
ELLER (http://salilab.org/modeller/).198,199 Wiltgen
et al.200 performed homology modeling to predict the
structure of 65-kD GAD65. Initially they performed
BLAST to compare the queried sequence of GAD65
via pairwise comparison, resulting in a list of align-
ments showing varied homologous sequences. The
best alignment with the lowest expectation value
(E-value) is selected. Simultaneously, the crystal
structure of DOPA decarboxylase of pig kidney with
and without inhibitor carbidopa is downloaded. The
active site of GAD 65 is determined via sequence
alignment. Moreover, a clear picture of the antigenic
determinants is obtained through the visualization of
the epitopes on the GAD65 molecular surface. Thus,
this process could facilitate our understanding of the
immune response that is disrupted by the passive ad-
ministration of molecules like DOPA. Assmann et
al.59 performed a bioinformatics analysis and found
that almost 11 circulating miRNAs are dysregulated
in T1D patients: miR-1275, miR-21-5p, miR-375,
miR-24-3p, miR-342-3p, miR-100-5p, miR210-5p,
miR-181a-5p, miR-150-5p, miR-146a-5p, and miR-
148a-3p. They regulate immune pathways such as
MAPK, Jak-STAT, PI3K-Akt, NF-κB, TNF, TCR,
insulin, and TLR signaling pathways. However, fur-
ther evaluation is necessary to determine the specific
role of each miRNA in pancreatic islets and β-cell
functioning.
Sequence alignment is used to identify the simi-
larities among primary sequences related to function
and structure in DNA, RNA, and proteins. Pairwise
and multiple-sequence alignment are widely used
techniques by the researchers. Rao et al.201 constructed
a phylogenetic tree to determine the relationship be-
tween diabetic complications of cardiomyopathy and
pathogenically altered calcium homeostasis. Simi-
larly, Rao et al.202 constructed a phylogram tree based
on the protein data available from NCBI for deter-
mining the genes involved in the evolution of obesi-
ty-related diabetes. They used the Clusta1W tool to
perform multiple sequence alignments.
Various new studies are focusing on identify-
ing novel biomarkers using sequence alignments.
For instance, Zhang et al.203 potentiated proteomics
technologies to detect novel biomarkers involved
in the pathogenesis. They used global liquid chro-
matography-mass spectrometry-based proteomics
analysis for almost 25 serum proteins. In addition
to the insulin autoantibodies, they identified cer-
tain peptide markers from peptide assays. These
peptide markers are independent of autoantibody
markers. Their results were negative for expression
but positive for the peptide NIQSLEVIGK, which
matches the diabetic group. Moreover, they have
taken 2 polypeptides from the platelet-based protein
precursor (PPBP), which is upregulated in T1D pa-
tients. These peptides include EESLDSDLYAELR
and NIQSLEVIGK of PPBP. These researchers
further performed sequence alignment with these
peptides and proteins CTAPIII, β-TG, NAP-2, TC-
1, and TC-2. They identified a similarity between
NIQSLEVIGK and all proteins, although EESLDS-
DLYAELR shows similarity only with CTAP III and
TC-2 and β-TG. Meanwhile, TC-1, an antibacterial
protein released at the response of innate immunity
due to the active platelet α-granules, and NAP-2
are the activators of neutrophils released from the
proteolytic cleavage of CTAP III and PPBP. Addi-
tionally, they also determined SERPING, a plasma
protease C1 inhibitor as a sensitive marker for the
detection of T1D. Thus, they classified the samples
obtained from the control group and T1D patients
with 100% sensitivity and specificity of both the
PPBP and C1 inhibitors. In addition, their findings
suggest that T1D occurrence was also due to the
dysregulation of the innate immune response.
The simulation method is another technique
used in the field of bioinformatics for tracking the
pathophysiological process involved in various dis-
eases. The glucose-insulin simulation study could
be an essential process for diabetes research. Recent
simulation methods used for T1D include the mini-
mal model of Bergman under intensive care, which
is based on intravenous glucose tolerance test.204
This method includes sampling glucose and insulin
concentrations in plasma after a glucose intravenous
injection. In addition, a new meal simulation method
is being used to compare the physiological processes
in healthy individuals after a given meal.205
Certain techniques called new-generation se-
quencing (NGS) include sequencing millions of
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy255
DNA fragments either for an entire genome or for
a definite site using computational techniques. In
T1D, the presence of DRB3*02:02 was identified
on the DRB1*03:01 haplotype using NGS tech-
nology, which showed a risk for T1D.206 Various
NGS methods include single-molecule real-time se-
quencer (SMRTTM), VisiGen Biotechnologies, and
Nanopore DNA sequencer. However, they require
advanced bioinformatics techniques for analysis and
determining the cause of disease.207 Mathieu et al.208
explained ongoing projects in Europe, including
Global Platform for the Prevention of Autoimmune
Diabetes (GPPAD; www.gppad.org/de) and INNO-
DIA, which have enabled biomarker discoveries
based on patient samples such as urine and stool.
INNODIA is a recent process that aims to facilitate
innovative ideologies for understanding and pre-
vention. It collects samples from newly diagnosed
T1D patients and first-degree relatives to elucidate
the pathogenesis and novel biomarkers. The clini-
cal data collected from omics and sequencing are
secured in the INNODIA database, which forms a
platform to support in silico modeling of T1D.
Bioinformatics is also widely used for drug
designing and drug delivery. Kir6.2 is an integral
membrane protein and a subunit of the ATP-sensi-
tive K+ channel that allows the K+ flow from outside
of the β-cell to the inside controlled by G-proteins
and sulfonylurea receptor (SUR). However, muta-
tion in both Kir6.2 and SUR causes the permanent
opening of KATP channel and closing of calcium
channel. Jagadeb et al.209 reported the interaction of
various phytochemicals including curcumin, pteros-
tilbene, piperine, and genistein with Kir6.2. The
mutated amino acid residues found include H46Y,
Y330S, Q52R, R201H, G53D, L164P, K170T,
R50Q, C166T, and V59M. However, due to the
nonavailability of the crystal structure of Kir6.2,
they first designed a secondary structure using an in
silico approach. All the phytochemicals that exhib-
ited an inhibitory effect on the expression of Kir6.2
were docked at an ATP-docking site that included
residues Ala-178, Ala-300, Phe-18, and Leu-181.
Hydrogen bonds formed between Arg-301 and
Phe-183 in the binding pocket of mutated Kir6.2.
Curcumin is a phytochemical that plays a crucial
role in inhibiting pathogenesis of various diseases
Volume 39, Issue 4, 2019
like diabetes and cancer. A novel derivative of cur-
cumin C66 was found to decrease hyperglycemia
promoted the inflammatory response and apopto-
sis by inhibiting JNK activity. JNK plays a crucial
role in regulating apoptotic effects of active TNF-α
cells in cardiac cells. The dysregulation causes dia-
betes-associated cardiomyopathy. Furthermore, Pan
et al.210 identified an interaction of the C66 and JNK
proteins validated with SP600125 and using 2 JNK
proteins (JNK1 and JNK2). The C66 was found in
the hydrophobic region in the JNK1 receptor bind-
ing pocket; the residues involved are Leu-168, Ile-
32, Val-40, and Ile-52. With JNK2, the binding
occurred with 3 hydrogen bonds with Arg involved
in the pocket. Thus, C66 showed higher binding af-
finity with JNK2 (IC50-2.72) than JNK1 (IC50-81.9),
which exhibited increased inhibition and anti-in-
flammatory effects. This research furthers the basis
for the drug designing and drug discovery related to
diabetic therapy.
XII. ADVANCED TECHNOLOGIES FOR THE
MANAGEMENT OF T1D
Several novel technologies are now available for
the management of T1D that mainly adopt a stan-
dard of care as the intensive insulin therapies as per
the publication of landmark 1993 Diabetes Control
and Complications Trial.211 Glycemic conditions are
properly maintained via advanced glucose monitor-
ing and insulin delivery. The most widely used tech-
niques for the management include blood glucose
meters, continuous glucose monitors, insulin pumps,
and a combination of monitors and pump that are
additionally automated driven by the algorithms.
Insulin pump therapy is administered via injection
or continuous infusion, whereas intensive insulin
therapy is administered via subcutaneous injection
of long-acting basal insulin given once or twice per
day. Additionally, a fast-acting insulin is given at
meal time. At present in this electronic world, the
advancement for insulin injections is replaced by
the insulin pens and are potentiated because they
are retrofitted with the smartphone applications that
offer data about a patient’s blood glucose, physical
activity, and food intake. Blood glucose meters212
are user friendly and can be used at home, where
256 Dariya et al.
patients can self-manage their insulin regimens.
Moreover, the insulin delivery can also be auto-
mated using an insulin delivery system, artificial
pancreas, and closed loop. These techniques have
a built-in complete glucose monitor with an insu-
lin pump and algorithm for the delivery of insulin
according to past insulin delivery data. Thus, more
advanced systems are developed and expected to
control both hyper- and hypoglycemic levels.213–216
However, exogenous therapy is for shorter periods
and for recurrent episodes of hypoglycemia. There-
fore, replacing the functionality of β cells to create
a normal glycemia level endogenously is essential.
Transplantation of pancreas from a healthy individ-
ual can bring glucose to normal levels. Transplan-
tation resulted in reducing autoimmune responses
and diabetes-related complications like micro- and
macroangiopathy, with improvement in the survival
rate of the patient.217 However, these procedures
present high risk for surgical complications. Novel
approaches include extrahepatic site of implementa-
tion, immunotolerance, and using substitutes for is-
lets. However, these procedures still require clinical
testing in advanced phases.
XIII. CONCLUSIONS
Type 1 diabetes (T1D) is a serious chronic autoim-
mune disease. The T1D phenotype remains a target
and treatments are remain imperfect. Therefore,
perfect characterization of the etiology of diabetes
to support further therapeutic developments is es-
sential. Genetic and autoimmune factors are always
risk predictors, although vitamin D deficiency and
drinking cow milk at an early age are still being in-
vestigated. Additionally, viral factors may also be
causative triggers. Researchers have started work-
ing on vaccines on the premises that inequity in
the gut microflora may cause certain pathogeneses
(like T1D) and, thus, that microbial supplements
and probiotics released from the gut microbiota
would reduce the risk of T1D to certain extent.
Moreover, the efficient classification of biomark-
ers based on the heterogeneity of the patient pop-
ulation for diagnosing, monitoring, and preventing
disease is essential. Although dynamic genotyping
has been performed for multiple autoantibodies as
biomarkers, the appropriate prediction of T1D re-
mains challenging. ‘Omics’ technology is now used
for detecting and validating various biomarkers.
Circulating methylated DNA is a promising facet of
the detection of dead β cells to predict T1D progres-
sion. The detection of biomarkers at every stage of
the disease along with stratified highest risk factors
potentiates the novel therapeutic procedure. Addi-
tionally, the PTMs like C- peptide have attracted
research to assess the dysregulation of β cells. Ad-
vanced proteomic techniques are currently being
used to identify and validate β-cell biomarkers.
Circulating exosomes, including GAD65, proinsu-
lin, and IA-2, impair phenotyping and can also be
used as predictive biomarkers. Thus, classifications
of biomarkers performed at novel stages provide a
superficial taxonomy of T1D and frame the clini-
cal trial designing. In addition, aberrantly activated
signaling pathways, mitochondrial dysfunction, and
impaired metabolism of glucose and cholesterol are
the primary mechanisms for diabetic complications
that are under investigation for T1D therapy. There-
fore, a profound study on the role of proteins and
their molecular mechanisms would dramatically re-
duce T1D-related complications. The pathogenesis
of T1D is highly confounded, and developing drugs
do treat this disease is challenging. The molecular
description of signaling pathways involved in the
progression of disease is essential for the develop-
ment of personalized drug development and novel
drug discoveries. Many more advances in the field
of genetics, epigenetics, and detection of autoanti-
gens are needed to drive novel methods of diagnosis
and therapy. T1D also enhances the risk for the pro-
gression of various other autoimmune diseases for
patients who have T1D from adolescence. T1D with
other autoimmune complications prejudice the glu-
cose metabolism and hinder insulin therapy. Contin-
uous monitoring of individuals with the autoimmune
diseases is essential to preventing damage to other
organs. Together, analyzing samples that are inter-
linked with the clinical data, developing technolo-
gies with integrated methods, and pioneering data
analysis would provide an enormous breakthrough
in the research of T1D. Recent advances in bioin-
formatics are effectively used for managing various
diseases like cancer and diabetes. The development
Critical ReviewsTM in Immunology
Computational Approaches for Immune Targets and Therapy257
of biological databases could form the foundation
for drug discovery and bioinformatics. Comput-
er-aided programs including modeling, homology
simulations, and docking have been widely used for
successful drug discovery and designing antidia-
betic drugs. Moreover, current research is providing
novel insights for the prediction and prevention of
the disease pathogenesis, and clinical trials to cure
T1D are underway.
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