Co esponding au ho : Hayam Aziz Mohammed
Copy igh © 2025 Au ho (s) e ain he copy igh o his a icle. This a icle is published unde he e ms o he C ea i e Commons A ibu ion License 4.0.
The in e play o en i onmen al and gene ic ac o s, along wi h he con ibu ions o
cellula and humo al immuni y, in he pa hogenesis o Type 1 Diabe es Melli us
Hayam Aziz Mohammed * and Ma wah Sabah Al aiee
Depa men o Biology, College o Educa ion o Pu e Sciences: Ibn Al-Hay ham, Baghdad Uni e si y, Baghdad, I aq.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1625-1631
Publica ion his o y: Recei ed on 11 July 2025; e ised on 20 Augus 2025; accep ed on 22 Augus 2025
A icle DOI: h ps://doi.o g/10.30574/wja .2025.27.2.2998
Abs ac
Type 1 diabe es Melli us is a long- e m au oimmune condi ion ha causes he be a cells in he panc eas ha p oduce
insulin o be des oyed. The p ecise causes o ype 1 diabe es a e unknown, bu i is belie ed o be a complica ed disease
b ough on by a mix o gene ic and en i onmen al ac o s ha igge an au oimmune esponse ha a acks panc ea ic
cells. HLA gene a ian s a e a signi ican cause o heigh ened suscep ibili y o he illness, in addi ion o en i onmen al
ac o s such as die , i amin de iciencies, and i al in ec ions. GAD65, IAA, and ZnT8 a e examples o au oan ibodies ha
migh appea yea s be o e symp oms de elop and a e ma ke s o he disease's p og ession. The immune sys em's
in ica e mechanisms o humo al and cellula apop osis and in lamma ion lead o he dea h o be a cells. App op ia e
he apy, ollow-up, and ea ly iden i ica ion o hese immunological ma ke s can enhance pa ien s' quali y o li e and
lessen he impac o he illness.
Keywo ds: Type 1 Diabe es; En i onmen al Fac o ; Gene ic Fac o ; Cellula and Humo al Immuni y
1. In oduc ion
Type 1 diabe es melli us (T1DM) is a ch onic disease cha ac e ized by he body’s inabili y o p oduce insulin due o
au oimmune des uc ion o panc ea ic be a cells. Insulin is he p ima y anabolic ho mone wi h c ucial e ec s on he
me abolism o glucose, lipids, p o eins, mine als, and g ow h. Type 1 diabe es p esen s as a sys emic diso de ma ked
by hype glycemia [1][2]. Al hough he disease is associa ed wi h au oimmune esponses a ge ing be a cells, he p ecise
causes and mechanisms o disease p og ession emain incomple ely unde s ood [3]. T1DM is a complex, mul i ac o ial
disease in luenced by bo h gene ic and en i onmen al ac o s a ec ing immune esponses agains be a cells. The main
suscep ibili y genes a e loca ed in he HLA egion on ch omosome 6, pa icula ly he majo his ocompa ibili y complex
(MHC) genes, such as HLA-DR3 and HLA-DR4, which play a pi o al ole in gene ic p edisposi ion, along wi h o he genes
like PTPN22 and CTLA4 ha egula e immune esponses. Despi e he impo ance o gene ic ac o s, en i onmen al
igge s, such as i al in ec ions o al e a ions in gu mic obio a, a e equi ed o ini ia e he disease p ocess [4][5].
E idence indica es ha changes in he gu mic obiome composi ion, including dec eased Bi idobac e ium and inc eased
Bac e oides, p omo e ch onic in lamma ion and impai immune balance, con ibu ing o he de elopmen o
au oimmuni y agains panc ea ic be a cells. Addi ionally, nu i ional ac o s such as i amin D de iciency, low omega-3
a y acid in ake, and high consump ion o dai y p oduc s, along wi h ea ly i al in ec ions (especially en e o i uses),
and high bi h weigh o o e weigh du ing in ancy, inc ease disease suscep ibili y [6][7]. In his con ex , he immune
sys em a ge s be a cell componen s by p oducing au oan ibodies ha do no di ec ly cause damage bu se e as
ma ke s o immune dys egula ion. These au oan ibodies play a c i ical ole in ea ly diagnosis and p edic ion o disease
be o e clinical symp oms appea [8]. The au oan ibodies mos commonly associa ed wi h ype 1 diabe es include insulin
au oan ibodies (IAA), glu amic acid deca boxylase 65 (GAD65) an ibodies, y osine phospha ase- ela ed IA-2
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an ibodies, zinc anspo e 8 (ZnT8) an ibodies, and isle cell an ibodies (ICA) [9]10]. These au oan ibodies ypically
ep esen he ea lies indica ion o he au oimmune p ocess, which may o may no p og ess o clinical disease, and can
be de ec ed yea s be o e symp om onse . Mul iple s udies ha e con i med hei impo ance in p edic ing disease onse
and p og ession, making hem i al ools o diagnosis and p e en ion [11]. Al hough ype 1 diabe es is a ch onic
immunological and physiological diso de , ea ly diagnosis h ough de ec ion o au oan ibodies, ea men adhe ence,
and con inuous ollow-up can signi ican ly educe complica ions and imp o e pa ien s’ quali y o li e. Gi en he complex
and mul i ac o ial na u e o he disease, a deepe unde s anding o he gene ic and en i onmen al ac o s in luencing
i s de elopmen is essen ial o de eloping mo e e ec i e diagnos ic and he apeu ic s a egies. This s udy aims o
e iew he cen al ole o HLA egion genes and associa ed immune mechanisms, as well as o e alua e he impac o
a ious en i onmen al ac o s on he ini ia ion and pe sis ence o au oimmune des uc ion o panc ea ic be a cells [12]
[ 13].
2. The Pa hogenesis o Type 1 Diabe es Melli us: Gene ic, Immunological, and En i onmen al
Mechanisms Wo king Toge he
2.1. Gene ic ac o s
Type 1 diabe es Melli us is a mul i ac o ial au oimmune diso de esul ing om a complex in e play be ween gene ic
suscep ibili y, immune dys egula ion, en i onmen al igge s, and gu mic obial composi ion. Gene ic p edisposi ion
emains a co ne s one in de e mining isk, pa icula ly h ough polymo phisms in genes ela ed o immune ecogni ion
and egula ion [14]. Human leukocy e an igen (HLA) class II alleles, especially HLA-DR3 and HLA-DR4, play a c i ical
ole in modula ing an igen p esen a ion o T cells. These alleles a e s ongly associa ed wi h heigh ened isk o
au oimmune esponses and a e consis en ly linked o T1D pa hogenesis. Despi e he p esence o high- isk geno ypes in
app oxima ely 90–95% o T1D cases, less han 5% o he gene al popula ion ac ually de elops he disease, indica ing
ha gene ic p edisposi ion alone is insu icien and equi es en i onmen al and immunological co ac o s [15]. Among
non-HLA genes, PTPN22, CTLA4, IFIH1, and IL2RA ha e been implica ed in modula ing T cell ac i a ion and immune
ole ance. The ansc ip ion ac o AIRE, c ucial o hymic exp ession o issue-speci ic an igens, con ibu es o cen al
ole ance by elimina ing au o eac i e T cells. Mu a ions in AIRE a e associa ed wi h au oimmune polyendoc ine
synd ome ype 1 (APS-1), which equen ly includes T1D. Simila ly, FoxP3, a ma ke o egula o y T cells (T egs),
ensu es pe iphe al immune homeos asis, and i s de iciency—seen in IPEX synd ome—o en leads o T1D among o he
au oimmune condi ions [16][17]. The gu mic obio a has eme ged as a signi ican en i onmen al ac o in luencing he
immune landscape in T1D. Dysbiosis, cha ac e ized by educed mic obial di e si y and al e ed abundance o speci ic
bac e ial axa, may comp omise in es inal ba ie unc ion and p omo e sys emic in lamma ion. S udies ha e shown
ha child en wi h high gene ic isk o T1D o en exhibi ea ly-li e shi s in gu mic obio a composi ion, including a
educ ion in Bi idobac e ium and Lac obacillus species, and an inc ease in p o-in lamma o y mic obes such as
Bac e oides [18]. These changes can impai he de elopmen o immune ole ance, enhance gu pe meabili y (“leaky
gu ”), and acili a e he ansloca ion o mic obial an igens o oxins, which may ac as igge s o isle au oimmuni y.
Mo eo e , sho -chain a y acids (SCFAs), such as bu y a e, p oduced by commensal bac e ia, a e known o enhance
T eg unc ion and in es inal ba ie in eg i y—bo h o which a e o en de icien in indi iduals p og essing owa d
T1DM [19].
In conclusion, he pa hogenesis o T1D is no dic a ed by gene ics alone bu is he esul o cumula i e in e ac ions
be ween gene ic a ian s, immunological imbalances, en i onmen al insul s, and gu mic obio a dis u bances. This
holis ic unde s anding is c ucial o iden i ying indi iduals a highes isk, de eloping bioma ke s o ea ly de ec ion,
and designing p e en i e s a egies ha may include immunomodula ion, mic obio a- a ge ed he apies, and ailo ed
li es yle in e en ions [20].
2.2. En i onmen al Fac o s in he De elopmen o Type 1 Diabe es (T1D)
A ailable e idence om animal and clinical s udies sugges s ha die a y ac o s ea ly in li e may play a ole in inducing
o supp essing he au oimmune esponse leading o ype 1 diabe es (T1D). Animal models, pa icula ly in NOD mice,
ha e shown ha a glu en- ee die du ing p egnancy o weaning may delay o educe he onse o he disease,
highligh ing he po en ial ole o glu en as an en i onmen al igge [21]. In human s udies, some epidemiological
analyses ha e shown ha in oducing glu en be o e 4 mon hs o age is associa ed wi h an inc eased isk o de eloping
isle au oimmuni y, compa ed o in oducing i be ween 4–9 mon hs o a e 9 mon hs [22]. Howe e , no all s udies
ag ee on his inding. O he s udies ha e no shown a clea associa ion be ween he iming o amoun o glu en
in oduc ion du ing he i s yea o li e and he isk o ype 1 diabe es, sugges ing ha die a y ac o s alone may no be
decisi e wi hou concomi an gene ic ac o s B eas eeding is a po en ial p o ec i e ac o , as he du a ion o
b eas eeding, pa icula ly beyond 6 mon hs, is associa ed wi h a sligh ly educed isk o de eloping au oimmuni y
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agains be a cells [23]. This is hough o esul om educed ea ly exposu e o o eign p o eins such as cow's milk
p o eins. A link be ween ea ly in oduc ion o cow's milk and an inc eased isk o diabe es has also been sugges ed,
al hough he e idence emains con lic ing. Vi amin D is also conside ed a nu ien ha may ha e a p o ec i e
immunological ole [24].
Some s udies sugges ha low le els o i in ea ly childhood may con ibu e o he s imula ion o au oimmune esponses.
Fu he mo e, i is hypo hesized ha ea ly i al in ec ions, such as hose caused by en e o i uses, may lead o abe an
ac i a ion o he immune sys em and he a ge ing o panc ea ic be a cells [25]. On he o he hand, i al in ec ions,
pa icula ly hose caused by coxsackie B i uses om he en e o i us amily, play a po en ial ole in inducing
au oimmuni y di ec ed agains panc ea ic be a cells. These in ec ions ha e been linked o he ac i a ion o in e e on
p oduc ion and inc eased exp ession o HLA class I molecules, making be a cells mo e suscep ible o a ack by cy o oxic
T cells [26]. These e ec s in e ac wi h gene ic p edisposi ion, as mu a ions in genes such as IFIH1 and TYK2 con ibu e
o ampli ying he in lamma o y esponse. Some da a indica e ha i al in ec ions may p ecede he appea ance o
au oan ibodies by a long pe iod, suppo ing he hypo hesis o hei ole in he onse o au oimmuni y.
As o he gu mic obiome, nume ous s udies ha e demons a ed an imbalance in i s composi ion in pa ien s wi h ype
1 diabe es compa ed o heal hy indi iduals [27]. T1D pa ien s a e cha ac e ized by educed bac e ial di e si y and
ins abili y, wi h lowe p opo ions o Fi micu es, Ac inobac e ia, and Lac obacillus, compa ed o inc eased p opo ions
o Bac e oide es, Clos idium, Veillonella, and Bac e oides. Also no ed is a dec eased abundance o Faecalibac e ium
p ausni zii, a bu y a e-p oducing bac e ium ha plays a ole in immune egula ion. This imbalance o en esul s om
cesa ean deli e y, an unbalanced ea ly die , o he use o an ibio ics in childhood, leading o he de elopmen o an
in es inal en i onmen un a o able o p ope immune sys em ma u a ion [28]. The gu mic obio a plays a c ucial ole
in egula ing in es inal pe meabili y and he immune sys em's balance be ween egula o y and in lamma o y pa hways.
Bene icial bac e ia such as Lac obacilli and Bi idobac e ial p omo e he p oli e a ion o T eg cells, which play a ole in
supp essing au oimmuni y, while p o eobac e ia (such as Esche ichia and Helicobac e ) p omo e Th1 and Th17
in lamma o y pa hways, which can con ibu e o be a cell des uc ion i ch onically p esen . The e o e, modi ying he
mic obiome's composi ion is a po en ial a ge o p e en i e in e en ion [29].
Expe imen s in NOD mice ha e shown ha a die ich in ace a e and bu y a e educed he de elopmen o diabe es, and
s udies using p obio ics (such as Bi idobac e ial and Lac obacilli) ha e demons a ed e icacy in educing disease-
causing immune esponses. Al hough animal s udies ha e shown p omising esul s, human clinical e idence emains
limi ed and inconsis en [30]. While he TEDDY s udy showed ha p obio ic adminis a ion in he i s weeks o li e was
associa ed wi h a educed isk o au oimmuni y in child en wi h a gene ic p edisposi ion, o he s udies ha e no
demons a ed a long- e m p o ec i e e ec o p obio ic use on he de elopmen o ype 1 diabe es [31].Based on hese
da a, i appea s ha he isk o de eloping ype 1 diabe es does no depend on a single ac o , bu a he on a complex
in e ac ion be ween gene ic p edisposi ion and en i onmen al, immunological, and nu i ional ac o s du ing ea ly
childhood. The e o e, u he longi udinal and sys ema ic s udies emain necessa y o accu a ely de e mine he impac
o hese ac o s and p o ide e ec i e p e en i e ecommenda ions.
3. The in ol emen o immuni y in Type 1 diabe es.
3.1. Cellula immuni y
Type 1 diabe es (T1D) is a complica ed au oimmune illness caused by dynamic combina ions be ween gene ic,
immunological, and en i onmen al a iables ha ul ima ely des oy panc ea ic be a cells, which p oduce insulin.
Among he p ima y immunological pa hways implica ed in disease p og ession, cell-media ed au oimmuni y is c i ical
o T1D's slow and p olonged pa hogenesis [33]. Cell-media ed immuni y, a c i ical componen o he adap i e immune
esponse, coexis s wi h humo al immuni y bu is p ima ily dependen on T lymphocy es, which include helpe T cells
(CD4+), cy o oxic T cells (CD8+), and egula o y T cells (T eg). An igen ecogni ion is he i s s ep in his immune
mechanism. An igens a e p esen ed o T cells ia majo his ocompa ibili y complex (MHC) molecules, which ac i a es
hem and causes he elease o p o-in lamma o y cy okines ha coo dina e a wide immune esponse, speci ically
a ge ing isle cell an igens [34]. When CD4+ and CD8+ T lymphocy es in ade he panc ea ic isle s in ype 1 diabe es,
hey coo dina e he immune sys em's killing o be a cells ia a a ie y o mechanisms, including di ec cy o oxici y and
he elease o in lamma o y cy okines, including in e leukin-2 (IL-2) and in e e on-gamma (IFN-γ). Be a-cell damage
is exace ba ed by hese eac ions, which also ac i a e na u al kille cells and mac ophages. Fu he mo e, Th17 cells
suppo he au oimmune p ocess and con ibu e o issue in lamma ion by sec e ing in e leukin-17 (IL-17) [35]. By
iden i ying be a-cell an igens p esen ed by MHC class I molecules, igge ing cellula apop osis by eleasing g anzymes
and pe o in, o ac i a ing he Fas/FasL pa hway, cy o oxic CD8+ T lymphocy es a e essen ial o he di ec des uc ion
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o be a cells. P o-in lamma o y cy okines such as IL-1, TNF-α, and NF-κB, which change he isle mic oen i onmen and
a ec be a-cell ac i i y, in ensi y hese damaging p ocesses [36].
Al hough egula o y T cells (T egs) a e essen ial o inhibi ing au o eac i e immune esponses, he e is a well-
es ablished de ici in he numbe and capaci y o hese cells in people wi h ype 1 diabe es. A pe sis en au oimmune
a ack on be a cells is made possible by his de ici , which comp omises immunological ole ance. Ea ly in he illness, T
cells a e unable o dis inguish be ween sel and non-sel , which causes CD4+ and CD8+ cells o become ac i a ed agains
endogenous an igens and s a s a chain eac ion o in lamma o y esponses [37]. I is hough ha apop osis, which is
media ed by he ac i a ion o caspase pa hways in ol ing cys eine-aspa ic p o eases, is he main cause o be a-cell
dea h in T1D. In bo h human in es iga ions and expe imen al models, apop o ic cell dea h is hough o be he p ima y
cause, while nec osis may also play a ole [38]. These apop o ic pa hways a e igge ed by au o eac i e T-cell in il a ion
and high le els o in lamma o y cy okines in he isle mic oen i onmen . Fas/FasL signaling o pe o in-media ed
pa hways can in e ac wi h be a cells, and bo h e en ually lead o be a-cell dea h. Cy okine sec e ion, howe e ,
con inues o be a key elemen o his damaging p ocess [39]. Acco ding o his opa hological analyses, insuli is is de ined
by he in il a ion o immune cells in o he isle s o Lange hans, including dend i ic cells, T cells, B cells, and
mac ophages. Long be o e diabe es mani es s clinically, his ch onic in lamma o y condi ion usually s a s. In he p e-
symp oma ic s age, e en in he absence o ob ious clinical symp oms, pa ien s ha e dys egula ed glucose me abolism
and isle au oan ibodies. Be o e hype glycemic symp oms appea , 70–90% o unc ional be a-cell mass mus be los , so
his "silen " au oimmune phase is a c ucial ime o comp ehend pa hophysiology and c ea e p e en i e measu es [40]
[ 41].
Figu e 1 Gene ics, en i onmen , and he immune sys em in e ac o cause ype 1 diabe es by des oying be a cells
[42]
3.2. Humo al immuni y
The body's immune de ense depends hea ily on humo al immuni y, which is mainly based on B cells ha p oduce
speci ic an ibodies ha a ge o eign an igens and ci cula e in bodily luids like blood and lymph. The abili y o hese
cells o ecognize an igens and gene a e a ge ed an ibodies is a co e unc ion o hese cells [43]. B cells wo k closely
wi h helpe T cells wi hin a egula ed immune esponse ha no mally dis inguishes be ween “sel ” and “non-sel .”
Howe e , his balance can be upse in au oimmune diseases, such as ype 1 diabe es, which causes he body o p oduce
au oan ibodies agains i s own issues, especially he be a cells in he panc eas ha p oduce insulin. In ype 1 diabe es,
he au oimmune esponse o en s a s ea ly in li e, yea s be o e clinical symp oms appea [44][45]. Acco ding o
esea ch, au oan ibodies agains isle cell cons i uen s such as zinc anspo e (ZnT8), insulin (IAA), glu amic acid
deca boxylase (GAD65), and y osine phospha ase (IA-2) a e c ucial biochemical indica o s o he ea ly iden i ica ion
o au oimmune al e a ions ha esul in he illness. Since gene dele ion s udies in animal models ha e shown a
signi ican educ ion in disease incidence, highligh ing i s c i ical ole in ini ia ing au oimmuni y, p oinsulin is belie ed
o be a p ima y au oan igen in his p ocess [46]. Despi e he ac ha au oan ibodies a e no di ec ly ha m ul in ype 1
diabe es, B lymphocy es a e essen ial because o hei abili y o deli e an igens. I has been demons a ed in NOD mice
ha illness p e en ion is achie ed by educing he abili y o B cells o p esen an igens while p ese ing an ibody
p oduc ion. Speci ically, NOD animals lacking T cell esponses o he isle au oan igen GAD [47][48] and B cells unable
o in e nalize isle an igens ia hei B cell ecep o s we e shielded om DT1 de elopmen . On he o he hand, i was
disco e ed ha in hese models, he selec ion o B cells wi h a high a ini y o insulin accele a ed he onse o diabe es.
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Acco ding o human esea ch, pa ien s' insulin- eac i e high-a ini y B cells lose hei abili y o ole a e insulin bo h
be o e and a e diagnosis. Pa icula ly in gene ically p edisposed popula ions, au oan ibody p o iling has eme ged as
a c i ical p edic ion me hod o iden i ying people a isk o de eloping ype 1 diabe es. GAD au oan ibodies usually
show up be ween he ages o 4 and 5, whe eas insulin au oan ibodies usually show up be ween he ages o 1 and 2. Age,
sex, and HLA-DR geno ype ha e been ound o ha e an impac on he o ma ion o au oan ibodies in la ge p ospec i e
coho s udies wi h o e 24,000 pa icipan s. In pa icula , he HLA-DR3 haplo ype is mo e ypically linked o GAD
au oan ibodies, while he HLA-DR4 haplo ype is mo e o en linked o insulin au oan ibodies. A he momen , he mos
p ecise model o o ecas ing he de elopmen o ype 1 diabe es combines gene ic isk sco es wi h he quan i y o isle
au oan ibodies ound [49]
[50]. Howe e , he i s cause o au oan ibody o ma ion is s ill unknown. Acco ding o ce ain heo ies, he au oimmune
p ocess may be s a ed by be a cell s ess o inju y, which could be he esul o i al in ec ions. This is co obo a ed by
ecen esea ch showing modes inc eases in pos p andial glucose le els abou wo mon hs be o e se ocon e sion,
which aises he possibili y ha be a cell mal unc ion may p ecede o possibly igge he o ma ion o au oan ibodies.
C ucially, he se e i y o he condi ion seems o be in luenced by he age upon diagnosis. Acco ding o s udies, child en
wi h DIT diagnosed be o e he age o se en had mo e B cell in il a ion in he panc ea ic isle s and had less unc ioning
be a cells han child en diagnosed la e . This inding is consis en wi h he heo y ha apid be a cell dea h and a mo e
obus immune esponse a e hallma ks o ea ly-onse ype 1 diabe es [51] [ 52].
4. Conclusion
Type 1 diabe es is an au oimmune disease caused by immunological dys egula ion, en i onmen al exposu es, and
gene ic p edisposi ion. The cause is no solely gene ic; isle -speci ic au oan ibodies and cellula immuni y also
con ibu e. Focused p e en i e measu es, con inuous moni o ing, and ea ly de ec ion a e c ucial o imp o ing pa ien
ou comes and slowing he disease's p og ession.
Compliance wi h e hical s anda ds
Disclosu e o con lic o in e es
No con lic o in e es o be disclosed.
Re e ences
[1] Zajec A, T ebušak Podk ajšek K, Teso nik T, Ške R, Čugalj Ke n B, Jenko Bizjan B, Šmigoc Schweige D, Ba elino
T, Ko ač J. Pa hogenesis o ype 1 diabe es: es ablished ac s and new insigh s. Genes. 2022 Ap 16;13(4):706
[2] Sun F, Yang CL, Wang FX, Rong SJ, Luo JH, Lu WY, Yue TT, Wang CY, Liu SW. Panc ea ic d aining lymph nodes
(PLNs) se e as a pa hogenic hub con ibu ing o he de elopmen o ype 1 diabe es. Cell & Bioscience. 2023 Aug
28;13(1):156.
[3] T an MT, Ciacchi L, Ciacchi L, Reid HH. Con eying he pa hogenesis o ype 1 diabe es o he blind, low- ision and
di e se needs communi ies h ough senso y s imula ion. Immunology and Cell Biology. 2024 May;102(5):341-
6.
[4] Qua in T, Mas and ea LD, Walke LS. Type 1 diabe es. The Lance . 2023 Jun 24;401(10394):2149-62.
[5] Kohil A, Al-Asmakh M, Al-Sha ai M, Te aneg a A. The in e play be ween die and he epigenome in he
pa hogenesis o ype-1 diabe es. F on ie s in Nu i ion. 2021 Jan 28; 7:612115.
[6] He de C, Roden M. A no el diabe es ypology: owa ds p ecision diabe ology om pa hogenesis o ea men .
Diabe ologia. 2022 No ;65(11):1770-81
[7] Minniakhme o I, Yalae B, Khusaino a R, Bonda enko E, Melnichenko G, Dedo I, Mok yshe a N. Gene ic and
epigene ic aspec s o ype 1 diabe es melli us: mode n iew on he p oblem. Biomedicines. 2024 Feb 8;12(2):399.
[8] Robe son CC, Rich SS. Gene ics o ype 1 diabe es. Cu en opinion in gene ics & de elopmen . 2018 Jun 1; 50:7-
16.
[9] Yahaya T, Salisu T. Genes p edisposing o ype 1 diabe es melli us and pa hophysiology: a na a i e e iew. a Xi
p ep in a Xi :2101.06680. 2021 Jan 17.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1625-1631
1630
[10] F omme L, Kahaly GJ. Type 1 diabe es and au oimmune hy oid disease— he gene ic link. F on ie s in
endoc inology. 2021 Ma 10; 12:618213.
[11] Mi al R, Camick N, Lemos JR, Hi ani K. Gene-en i onmen in e ac ion in he pa hophysiology o ype 1 diabe es.
F on ie s in Endoc inology. 2024 Jan 26; 15:1335435.
[12] S ene LC, Tuomileh o J. Epidemiology o ype 1 diabe es. Tex book o diabe es. 2024 Feb 7:41-54.
[13] Xu Y, Jiang J, L X, Li H, Yang D, Wang W, Hu Y, Liu L, Dong X, Cai Y. En i onmen - igge ed nanoagen wi h
p og ammed gas elease pe o mance o accele a ing diabe ic in ec ed wound healing. Chemical Enginee ing
Jou nal. 2024 Jan 1; 479:147645.
[14] Luo S, Yue T, Liu Z, Yang D, Xu M, Ding Y, Jiang W, Xu W, Yan J, Weng J, Zheng X. Gu mic obiome and me abolic
ac i i y in ype 1 diabe es: An analysis based on he p esence o GADA. F on ie s in Endoc inology. 2022 Sep 30;
13:938358.
[15] He old KC, Delong T, Pe digo o AL, Bi u N, B usko TM, Walke LS. The immunology o ype 1 diabe es. Na u e
Re iews Immunology. 2024 Jun;24(6):435-51.
[16] Ing Z, Li Y, Ma Y, Zhang X, Liang X, Zhang X. Le e age bioma e ials o modula e immuni y o ype 1 diabe es.
F on ie s in Immunology. 2022 No 2; 13:99728
[17] Szablewski L. Role o immune sys em in ype 1 diabe es melli us pa hogenesis. In e na ional
immunopha macology. 2014 Sep 1;22(1):182-91.
[18] Jacobsen LM, Newby BN, Pe y DJ, Posgai AL, Halle MJ, B usko TM. Immune mechanisms and pa hways a ge ed
in ype 1 diabe es. Cu en diabe es epo s. 2018 Oc ; 18:1-20.
[19] Eizi ik DL, Szymczak F, Mallone R. Why does he immune sys em des oy panc ea ic β-cells bu no α-cells in ype
1 diabe es? Na u e Re iews Endoc inology. 2023 Jul;19(7):425-34.
[20] Lokesh MN, Kuma R, Jacob N, Sachde a N, Rawa A, Yada J, Dayal D. Supplemen a ion o high-s eng h o al
p obio ics imp o es immune egula ion and p ese es be a cells among child en wi h new-onse ype 1 diabe es
melli us: a andomised, double-blind placebo con ol ial. Indian jou nal o pedia ics. 2025 Ma ;92(3):277-83.
[21] Du C, Whidde RO, Buckle I, Chen C, Fo bes JM, Fo he ingham AK. Ad anced glyca ion end p oduc s and
in lamma ion in ype 1 diabe es de elopmen . Cells. 2022 No 4;11(21):3503.
[22] Fel on JL, Redondo MJ, O am RA, Speake C, Long SA, Onengu -Gumuscu S, Rich SS, Monaco GS, Ha is-Kawano A,
Pe ez D, Saeed Z. Isle au oan ibodies as p ecision diagnos ic ools o cha ac e ize he e ogenei y in ype 1
diabe es: a sys ema ic e iew. Communica ions medicine. 2024 Ap 6;4(1):66.
[23] Zacca di F, Webb DR, Ya es T, Da ies MJ. Pa hophysiology o ype 1 and ype 2 diabe es melli us: a 90-yea
pe spec i e. Pos g adua e medical jou nal. 2016 Feb;92(1084):63-9.
[24] Tesau o M, Mazzo a FA. Pa hophysiology o diabe es. InT ansplan a ion, bioenginee ing, and egene a ion o
he endoc ine panc eas 2020 Jan 1 (pp. 37-47). Academic P ess.
[25] Sabe zadeh-A des ani B, Ka amzadeh R, Basi i M, Hajizadeh-Sa a E, Fa hadi A, Shapi o AJ, Taham ani Y,
Baha and H. Type 1 diabe es melli us: cellula and molecula pa hophysiology a a glance. Cell Jou nal
(Yakh eh). 2018 May 28;20(3):294.
[26] Baynes HW. Classi ica ion, pa hophysiology, diagnosis and managemen o diabe es melli us. J diabe es me ab.
2015 May 1;6(5):1-9.
[27] Szablewski L. Role o immune sys em in ype 1 diabe es melli us pa hogenesis. In e na ional
immunopha macology. 2014 Sep 1;22(1):182-91.
[28] Tomic D, Ha ding JL, Jenkins AJ, Shaw JE, Magliano DJ. The epidemiology o ype 1 diabe es melli us in olde
adul s. Na u e Re iews Endoc inology. 2025 Feb;21(2):92-104.
[29] Casu A, Bha heja A, The hi TK. Immunology and clinical app oach o adul -onse ype 1 diabe es. SMART-MD
Jou nal o P ecision Medicine. 2025 May 31;2(2):e111-8.
[30] Roep BO, T ee TI. Immune modula ion in humans: implica ions o ype 1 diabe es melli us. Na u e Re iews
Endoc inology. 2014 Ap ;10(4):229-42.
[31] Wållbe g M, Cooke A. Immune mechanisms in ype 1 diabe es. T ends in immunology. 2013 Dec 1;34(12):583-
91.
Wo ld Jou nal o Ad anced Resea ch and Re iews, 2025, 27(02), 1625-1631
1631
[32] Jaleel N. HLA class II Molecula Typing (Au oLIPA) and Se um le el o IL-17A in a Sample o I aqi Type 1 Diabe es
Melli us Pa ien s. Medical Labo a o y Depa men . 2011.
[33] Kahaly GJ, Hansen MP. Type 1 diabe es associa ed au oimmuni y. Au oimmuni y e iews. 2016 Jul 1;15(7):644-
8.
[34] Knip M, Siljande H, Ilonen J, Simell O, Veijola R. Role o humo al be a‐cell au oimmuni y in ype 1 diabe es.
Pedia ic diabe es. 2016 Jul; 17:17-24.
[35] Guye P, Semino a K, Luga M, Mangana o A, Vela de de la C uz EE, Ha ley R, Smi hmye ME, Speake C, Boni acio
E, Ken SC, James EA. T cell and au oan ibody ecogni ion o nucleus-associa ed isle au oan igens in indi iduals
wi h ype 1 diabe es. Diabe ologia. 2025 Jun 9:1-4.
[36] Niinis ö S, Cu hbe son D, Mie inen ME, Hakola L, Nucci A, Ko honen TE, Hyö y H, K ische JP, Vaa ala O, Knip
M, Sa ilah i E. High Concen a ions o Immunoglobulin G Agains Cow Milk P o eins and F equency o Cow Milk
Consump ion A e Associa ed wi h he De elopmen o Isle Au oimmuni y and Type 1 Diabe es—The T ial o
Reduce Insulin-dependen Diabe es Melli us (IDDM) in he Gene ically a Risk (TRIGR) S udy. The Jou nal o
Nu i ion. 2024 Aug 1;154(8):2493-500.
[37] Wang J, Wan K, Chang X, Mao RF. Associa ion o au oimmune hy oid disease wi h ype 1 diabe es melli us and
i s ul asonic diagnosis and managemen . Wo ld Jou nal o Diabe es. 2024 Ma 15;15(3):348.
[38] Golden GJ, Wu VH, Hamil on JT, Amses KR, Shapi o MR, Sada Japp A, Liu C, Pampena MB, Ku i-Ce an es L, Knox
JJ, Ga dne JS. Immune pe u ba ions in human panc eas lympha ic issues p io o and a e ype 1 diabe es
onse . Na u e Communica ions. 2025 May 18;16(1):1-6.
[39] Ajie M, an Heck JI, Janssen AW, Meije RI, Tack CJ, S iens a R. Disease du a ion and ch onic complica ions
associa e wi h immune ac i a ion in indi iduals wi h longs anding ype 1 diabe es. The Jou nal o Clinical
Endoc inology & Me abolism. 2023 Aug;108(8):1909-20.
[40] Roep BO, Thomaidou S, Van Tienho en R, Zaldumbide A. Type 1 diabe es melli us as a disease o he β-cell (do
no blame he immune sys em?). Na u e Re iews Endoc inology. 2021 Ma ;17(3):150-61.
[41] Xie Z, Chang C, Zhou Z. Molecula mechanisms in au oimmune ype 1 diabe es: a c i ical e iew. Clinical e iews
in alle gy & immunology. 2014 Oc ; 47:174-92
[42] Mau ais FX, an Ende PM. Type 1 diabe es: A guide o au oimmune mechanisms o clinicians. Diabe es, Obesi y
and Me abolism. 2025 May 15.
[43] Tomic D, Ha ding JL, Jenkins AJ, Shaw JE, Magliano DJ. The epidemiology o ype 1 diabe es melli us in olde
adul s. Na u e Re iews Endoc inology. 2025 Feb;21(2):92-104.
[44] Peakman M, San ama ia P. Au oan igen-Speci ic Immuno he apies o he P e en ion and T ea men o Type 1
Diabe es. Cold Sp ing Ha bo Pe spec i es in Medicine. 2025 Jun 1;15(6): a041598.
[45] Zhang Q, Liao J, Liu Z, Song S, Tian L, Wang Y. The immune ole ance ole o B egs in inhibi ing human
in lamma o y diseases, wi h a ocus on diabe es melli us. F on ie s in Immunology. 2025 Ap 30; 16:1565158.
[46] Onengu -Gumuscu S, Concannon P, Akolka B, E lich HA, Julie C, Mo ahan G, Nie as CR, Pocio F, Todd JA, Rich
SS. Type 1 diabe es gene ics conso ium. The Jou nal o Clinical Endoc inology & Me abolism. 2025
Jun;110(6):1505-13.
[47] Yu X, Liu C, Kuang Z, Song S, Tian L, Wang Y. Isle o ganoids: a new hope o isle ansplan a ion in diabe es.
F on ie s in Immunology. 2025 Jan 21; 15:1540209.
[48] Mo an MP, Omenn GS, Pie opaolo M. Immunology and gene ics o ype 1 diabe es. Moun Sinai Jou nal o
Medicine: A Jou nal o T ansla ional and Pe sonalized Medicine: A Jou nal o T ansla ional and Pe sonalized
Medicine. 2008 Aug;75(4):314-27.
[49] Na end an P, Es ella E, Fou lanos S. Immunology o ype 1 diabe es. Qjm. 2005 Aug 1;98(8):547-56.
[50] Al-Hussaniy HA, Albu ghai AH, Naji MA. Lep in ho mone and i s e ec i eness in ep oduc ion, me abolism,
immuni y, diabe es, hopes and ambi ions. Jou nal o medicine and li e. 2021 Sep;14(5):600.
[51] Ye Z, Li L, Yang L, Zhuang L, Aspa wa A, Wang L, Gong W. Impac o diabe es melli us on ube culosis p e en ion,
diagnosis, and ea men om an immunologic pe spec i e. InExplo a ion 2024 Oc (Vol. 4, No. 5, p. 20230138).
[52] Sub amanian S, Khan F, Hi sch IB. New ad ances in ype 1 diabe es. bmj. 2024 Jan 26;384.
