1.Introduction:
Earlier we had reviewed various aspects of Type 1 Diabetes(T1D)(,its etiopathogenesis,various immunotherapies used and how we could try to obviate the need of insulin ,role of empagliflozin addition ,role of ECV’s in treating complications associated with T1D ,role of gut microbiota and early life feeding,genes responsible (unpublished ),epigenetics in DKD [1-11].Here we decided to conduct a systemic review on  role of β cells in etiopathogenesis along with treatment directed towards  them.

1.1.Autoimmune Type 1 Diabetes:
Autoimmune Type 1 Diabetes(T1D)(also known as   Type 1a Diabetes) occurs  secondary to insulin deficit resulting from autoimmune modulated damage of pancreatic β cells[12] Usually it is discriminated from the <common Type 1b Diabetes,or idiopathic /non Autoimmune Diabetes,where insulin deficit and β loss  with no β cells Autoimmunity[13].There has been an escalation  all over the world  in the last few decades[14], as well as     although considered a paediatric disease ,recently escalating no of young adults  have got diagnosed[1,3].An experience in children as well as    adolescents /youth with T1D usually there are problems with  insulin dosing for sustainance  ideal glycaemic regulation as their age advances.Thus long duration Diabetes- associated  complicationslike Diabetic    Nephropathy (DN),  Neuropathy,retinopathy   might be seen  in their lifetimes[12].Moreover ,inspite of significantly    better insulins ,that have escalated lifespan  of people living   with   T1D,escalating financial barriers are there limiting affordability  in a lot   of countries [15],with a total greater risk of cardiovascular disease (CVD) ,the major cause of mortalityin T1D people[16] .At present no therapy exists to avoid /cure T1D ,with /day delivery of insulin –only safe ,efficacious managing method .Hence ,besides the clinical care continuing ,an immediate requirement exists for a more extensive T1D pathogenesis as well as     generate  avoidable treatment as well as    curable ones.

Methods:
Thus Here we conducted a systematic review utilizing search engine pubmed,google scholar ;web of science ;embase;  Cochrane   review  library  utilizing  the MeSH terms  like; Type 1 Diabetes(T1D ;beta cell in etiopathogenesis of T1D;Immunotherapies ;role of Unfolded proteins response(UPR);role of senescent β cells ; Role of Type 1  Interferon  ;DNA methylation;PDL1 ;Little insulin  generation  by αcells besides glucagon ;other endocriner cells of pancreas ;Role of autophagy;other mechanisms like apoptosis ;necrosis in  β cell  demise ; endoplasmic reticulum (ER)stress  ;Terminal  UPR;Advanced UPR;EM alterations in mitochondria of islet β cell;Endotype;heterogeneity  in T1D; of latent autoimmune Diabetes in Adults(LADA) ;Immunotherapies ; β cell therapies ;combination of 2 therapies;DDR;Senolytics;Bcl2;Bcl –XL; circulating cell free DNA  (cfDNA) ; Histone  mimic suppression of inflammation;BET Inhibitors(Molibresib); Epigenetics  modulation of macrophages and β cells; Tauroursodeoxycholic acid(TUDCA), Verapamil(TXNIP inhibitor) Imatinib  (IRE1α- ABL inhibitor   from  1950 to 2021 till date.

Results:
We found a total of 300 articles out of which we selected 135 articles for this review.No meta-analysis was done.

2.T1D pathogenesis - T1D Stages:
In T1D clinical heterogeneity is believed to occur secondary to various environmental exposures  at the time of generation as well as     genetic factors ,each of which carry a major part in bringing about β cell autoimmunity[14,19].Marked refining of models  utilized for the natural history  of  T1D  has been done in last decades  along with consensus view has been generated[18-20].3 separate clinical Stages of disease  propagation have been observed,though the time   as well as      initiation of every stage differs.At the time of the earliest Stage, patients are asymptomatic, as well as      due to genetic proneness  along with environmental  triggers β cell autoimmunity against β cell antigen  ,usually insulin[INS], glutamic acid decarboxylase( GAD65)  ,Islet antigen2(IA2) as well as      ([21]ZnT8).This early asymptomatic stage  can antecede  a T1D for yrs , as well as       escalating  amount of   autoantibodies associates well with escalated chances of T1D initiation [22].  In case of newly generated  risk scores that include genetic ,epidemiological  a;long woith immunological factors  ,that can markedly anticipate  the chance of T1D  initiation in children  among 2-8yr ages [23]ii) Stage 2 possesses  properties  of reducing   β cell function as well as     /or mass  as seen by aberrant glucose tolerance test(GTT) as well as      in certain instances mild  hyperglycemia[12]. Nevertheless,   overt   hyperglycemia   as well as      the typical DM   symptomatology  of polydipsia,  polyuria, as well as     polyphagia are missing.Recent proof  points that β cell impairment instead of totally β cell mass getting depleted  during this duration ,might be the key  factor for disease propagation[24].Ultimately in the  Stage 3, propagation   towards becoming totally symptomatic ,in which case  which functional  β cell  mass is not enough  to take care of the  body metabolic  requirements  resulting in constant hyperglycemia  as well as    the typical symptoms of diabetes mellitus (DM)  with or without diabetic ketoacidosis.

Intriguingly,a honeymoon  duration has been detailed  in about 50% of new onset pediatric  patients where the  symptoms appear to become better  as well as      clinical remission  of DM on the 1^st delivery of insulin that was followed by   reduction in insulin  dosage[25]. Nevertheless,  this phase is short lasting as anticipated ,mostly remaining for a few mths  as well as     patients  needing again insulin.This event is not well understood,  but might point to avenues for correct timing of treatment   to get β cell function retrieved in the long time following  diagnosis[26].  Inspite of initially thought that all β cells get damaged in T1D, nevertheless,  recent work points  that even in well proven T1D(greater than 3yrs following  diagnosis ),pro insulin liberation continues for yrs in practically all patients  [27] as well as     a big part of β cells persist in a lot of patients [28-30].These findings  are promising  for actions for recovering  β cells way following  diagnosis   .

2.2A Disease implicating immune system as well as   β cells-T1D:
T1D has been treated in the form of a Disease implicating immune system[31],in which β cells act as the passive targets  that get damaged by a complicated autoimmune event that is modulated by self-reactive cytotoxic CD4⁺ as well as     CD8⁺ T Cells that gets support via  innate immunity.In view of this highlighting,clinical interventions to avoid   as well as     treat  T1D concentrated on  immune  targeting treatment,  certain of which demonstrated advantageous  effects[32,33].Like a recent   clinical trial utilizing nondepleting antiCD3   antibody(teplizumab),that targets T cells ,in T1D  patients relatives  who themselves had a great chance of generation   of Disease(≥2 autoantibodies as well as     initial signs of aberrant glycemia )resulted in a   3yr median postponement  in the propagation towards T1D initiation  in contrast to  placebo[33]. Nevertheless,  the precise mode  of action of teplizumab are still not  known , as well as     this antibody thought to be therapeutic  further had minimal action in certain patients(like nonresponders)[33].Akin to that a recent trial  utilizing  golimumab,  that is  a monoclonal  as  tumor necrosis factor alpha(TNFα) antibody,resulted in escalation of residual  β cell function as well as     decreased utilization of  insulin in new onset  pediatric  as well as     young adult   patients  with T1D in contrast to placebo[34].This study  further documented  an escalated amount  of hypoglycemic processes ,besides escalated times of infections in golimumab patients[34]  Hence ,whereas certain immunotherapies  can postpone  propagation of disease  at the time of stage2 or even following stage3 initiation,there are certain  patients  who don’t respond  as well as     sometimes unanticipated results get encountered following  systemic  immunomodulation.  Lots of immunomotherapy   clinical trials for new onset T1D or avoidance of T1D/postponement are ongoing that are immune modulating antibodies, cytokine,vaccines as well as    regulatory T cell  treatment[35,rev byus ref 4,5].

Generating from the typical posit of T1D as an autoimmune disease, escalating proof points to the thought that β cells impairment is equally key like the autoimmune event, along with T1D being a disease of the β cells or islets [35,36]. Genome –wide association study (GWAS)  point that main polymorphisms  other than human leukocyte antigen(HLA)   complex  which have a correlation with T1D are located in genes that we know are expressed in β cells ,that includes INS gene by itself[37].In the last few yrs watching  these T1D patients  clinically point to the belief that  of continuing  β cells impairment before the diagnosis, as well as     β cells mass  as well as      function that continues to be present  despite the T1D  getting established,yrs  following  diagnosis   [16,17,38].Hence a newer  stress on β cells drug  treatments  might become promising   method to decrease β cells demise ,get the β cells  function  back along with avoiding T1D initiation at the time of stage 2  or early  into stage 3 of the disease[16].Here some of modes  which bring about  various types of β cells impairment at the time of stage 2  or stage 3 of T1D initiation as corroborated by mouse as well as     human studies,that includes β cells apoptosis,  senescence as well as     other impaired states with emphasis on clinical translation  actions   as well as     avenues for targeting these particular pathways.  Further the probability of combination of β cells drug treatments   with immunotherapy for T1D avoidance with the knowledge of continuous reexploration of T1D causation that would be necessary for optimizing the efficacy of every kind of treatments.

2.3β cells impairment in T1D:

2.3A.β cell   Endoplasmic Reticulum Stress, Apoptosis,Unfolded Proteins Response: 
Probably the best  evaluated  state of  β cells impairment at the time of etiopathogenesis of T1D is endoplasmic reticulum (ER)stress resulting in apoptosis[39,review in 40](figure1A) .Apoptosis by definition is a sort of programmed cell death,that gets triggered  by different modes  like internally   along with   irrecoverable cell injury (known as   intrinsic pathway),or externally  due to surface receptor crosstalk   with immune cells(extrinsic pathway) or due to perforin –granzyme pathway[41],[rev in detail ref 42].

Since β cell face great need for insulin development, processing, folding  along with liberation, metabolic as well as   immune –modulated stress  are thought to directly involve the capacity to maintain these events[30]. secondary to  this  a  main etiology of Apoptosis   in  β cells   is ER)stress   modulated   activation  of  the loss of  Unfolded proteins response(UPR)[43].Hence reduction in Ins1  gene dose  enhances  β cells    ER  function   just for a little time as well as      removes basal   UPR stress in mice [44].This UPR  represents a 3-branched system  which can aid cells to sustain homeostasis(adaptive  UPR) or make them to  undergo Apoptosis(terminal UPR)[45]. Adaptive UPR signalling  aids β cells    to meet with the stress of   Unfolded /misfolded proteins in the ER as well as recoup ,while a terminal UPR takes place if there is too high or continuous  stress,stimulating apoptosis[46](figure 1A).

Legend for Figure 1:

Courtesy ref no-40-Molecular pathways and therapeutic targets for beta cell unfolded protein response (UPR)-mediated apoptosis and senescence in type 1 diabetes (T1D). (A) Beta cell apoptosis in T1D results from persistent endoplasmic reticulum (ER) stress that leads to activation of UPR master regulators IRE1α, PERK and ATF6. IRE1α mediates its functions through its RNAse and kinase activities that are potentiated by the Abelson tyrosine-protein kinase (ABLs). The balance of each UPR regulator dictates the outcome on beta cell fate. Unrelieved ER stress signals through IRE1α and PERK and shifts the pathway towards a terminal UPR and apoptosis mediated by thioredoxin interacting protein (TXNIP), whereas ATF6 is the major mediator of adaptive UPR leading to beta cell survival. Clinical trials in new onset adult T1D patients have used Verapamil, Imatinib or tauroursodeoxycholic acid (TUDCA) to attenuate terminal UPR and apoptosis and/or enhance adaptive UPR to delay the decline in residual beta cell function. (B) Beta cell senescence in T1D may be initiated by unresolved DNA damage (although the precise triggers of DNA damage remain unknown). A persistent DNA damage response (DDR) in beta cells is indicated by gH2A.X which is mediated by ATM. DNA damaged beta cells show activation of cyclin-dependent kinase inhibitors p21 and p16, which enforce a senescent growth arrest. Senescent beta cells upregulate the antiapoptotic protein Bcl-2 and develop a senescence-associated secretory phenotype (SASP). Small molecule inhibitors including senolytic compounds targeting Bcl-2 (ABT-199, ABT-737) or suppressing SASP at the level of gene expression (iBET-762) mitigate the deleterious effects of accumulated senescent beta cells in NOD mice and prevent T1D. These drugs have not been tested in clinical trials for T1D. The white circles and the β symbol indicate the nucleus, while the purple structure is the ER and black dots indicate insulin granules.

Despite concentration of recent work  on   terminal UPR    signalling   as the main mode that 

stimulates β cells   apoptosis,  proof from the largely evaluated non obese diabetic(NOD)   mouse model of human T1D[47].points that  β cells  undergo  apoptosis as well through combination of extrinsic pathway   as well as      perforin –granzyme pathway  that gets directed via cytotoxic   T Cells[48,49].Akin to that a lot of studies on human donor pancreatic tissue  have validated  the thought that β cells   get  damaged  in a heterogenous manner over the  pancreas by CD8⁺ T Cells- modulated cytotoxicity[28,50].

A different type of  β cells   demise ,pointed to be implicated is necrosis[39],that is a lower type of cells   demise occurring  secondary go exaggerated injury ,where cells get broken down with intracellular    components getting liberated in the extra cellular   surroundings ,that stimulates immune activation  along with inflammatory responses [51].This is in  in contrast to   what is believed to  take place at the time of  apoptosis,since apoptotic cells   classically possess v short life as well as     get deleted by phagocytosis,  resulting in tissue remodeling[39,51].Although necrotic β cells   demise appears a lucrative reasoning  for the liberation of     auto antigen as has been posited [52],the proof for necrotic β cells   demise as a mode  in T1D remains not  conclusive.

One main query in this field involves which kind of β cells   demise is the predominant one in T1D, as well as    an if β cells   demise is usually persistent, relapse-remitting or totally as per the cause   as well as     based on the situation[53]. Intriguingly,in a recent  study utilizing  DNA  methylation in the form of a   biomarkers for circulating cell free DNA  (cfDNA) that initiates in β cells   observed no proof  to validate  β   cells   demise that is ongoing(with death measured as  β cells   obtained  cfDNA in serum)in seroconverted subjects or the ones with recent onset  or fully developed  T1D,while the same bioassay  had great  sensitivity to pick up  β cells   demise seems a promising   way following  islet transplantation [54]. Hence different kinds of  β cells   demise during the generation of T1D,whichever they might be ,either vary  from the ones during islet transplantation or are just not occurring persistently .With the broadening of our insight into  cells   demise mode [36] it would be significant to find the extra pathways  of β cells   demise in T1D.

2.3B. Unfolded proteins response modulated   β cells   Apoptosis-Pathways:
In case of β cells adaptive as well as , terminal UPR get kept in a balance that  is downstream of  ER stress. ER stress  stimulates the  tripartite UPR signalling pathways that implicates the master controllers  inositol requiring enzyme -1 alpha(IRE1α),PKR-like ER Kinase(PERK) along with activating transcription factor6(ATF6),every one of that controls the apoptotic  vis a vis survival fate outcome[43].Noticeably , mRNA as well as     proteins  markers of ER stress along with UPR stimulation  in β cells    are obvious in the initial stage prediabetic   NOD mice along with human T1D donor pancreas sections[55].On continuation of  ER stress or beyond reproach a transfer from adaptive as well as  , terminal UPR through IRE1α or PERK-based  stimulation of the redox protein  thioredoxin –interacting protein(TXNIP)in β cells    [46,56](figure1A).For triggering the intrinsic  apoptotic pathway in β cells,  TXNIP stimulation is necessary [46,56].As per this , terminal UPR as well as     apoptosis in β cells can be avoided  utilizing small molecule inhibitors  that target  the RNAse action of IRE1α or  its binding colleague,Abelson tyrosine protein kinase (ABL )[57].Current genetic proof  points that IRE1α further regulates  β cell  identity, as well as     β cells particular knockout  of this UPR-modulator  confers protection against T1D in case of NOD mice[58].Akin to that Txnip  knockout  avoids the apoptosis getting induced  in rodent β cell   line as well as     islets ex  vivo under situations of continuing ER stress,like escalated glucose[59].

3.1. UPR Treatment in T1D-Clinical Trials:
Clinical Trials that were evaluating  β cells-aimed treatments for T1D(like where β cells represent the primary target  of the experimental substance,excluding transplantation)are occasional.Since November 2020 on the clinicaltrials.gov website there were more than 2100 interventional trials(inclusive of all trial statuses) that are noted,but only roughly 100 of them implicate  β cells as targets of drugs,maximum of whom are repurposing agents ,at present being utilized for T2D. Interventional Clinical Trials using small Molecule agents(besides standard insulin regimens) to ameliorate    β cells apoptosis in T1D-in adults(≥18yrs old) have demonstrated beneficial initial outcomes  in small cohorts .A  phase II placebo controlled Trials utilizing  daily Verapamil(TXNIP inhibitor) with recent onset Type 1 diabetes in adult  subjects  >12mths(NCT 02372253) illustrated escalated conservation of β cells function,decreased hypoglycaemic processes  as well as     reduced insulin needs[60](figure1A). Nevertheless, the size of the study  was quite small(n=11 patients  for every treatment group) as well as     further documented a high rate of GIT adverse actions as well as     nausea ,thus it was not clear if the drug  might be tolerated  Specifically by paediatric population.Akin to that a recent Clinical Trial that  utilized  Imatinib  (IRE1α- ABL inhibitor)in recent onset Type 1 diabetes patients(NCT 01781975) illustrated partial conservation of β cells function  in contrast to  placebo (unpublished study) ](figure1A). Nevertheless,a wide range of side actions got documented as well as     happened  more often in the Imatinib-dosage group ,that were clubbed widely as gastrointestinal tract (GIT)  ,skin,respiratory ,cardiac,endocrine ,infections that points to a broad category of targets.Actually it was recently documented  that besides terminal UPR    signalling, Imatinib further directly  influences insulin liberation from  β cells[61] along with facilitates Reactive oxygen species(ROS)scavenging via B cells in NOD mice,an action that is necessary for  reversing of Diabetes[62].Thus it appears one has to gain a lot of further knowledge with regard to this drug.

 Terminal UPR     as well as     apoptosis might further be avoided by escalation of the capacity of β cells to deal with Unfolded proteins. Tauroursodeoxycholic acid(TUDCA),that is a bile acid obtained component works as an ER stress inhibitor along with protein chaperone[63] as well as     avoids Diabetes in the NOD mouse model  in an ATF6 based way[64] ](figure1A).Noticeably TUDCA –associated acids have been utilized  in a safe manner in infants along with children  for a little time now  in the form of therapy of different hepato-biliary diseases’[65],pointing that they would be safe for the paediatric subjects.A   phase II placebo controlled Clinical Trial for  TUDCA in recent onset Type 1 diabetes in adult  subjects(NCT 02218619)got finished recently ,though outcomes are still to get published.This studies observations would be significant in yielding more Clinical proof  for the capacity of UPR inhibitor therapies for escalation of β cell survival  as well as     function  in   T1D.Whereas  these studies are attractive ,a crucial property of these drug treatments  is their need  for continuous delivery for hampering their targets  as well as     be efficacious (daily dosage regimes got utilized in these trials).This type of regimen usually makes the duration along with robustness the maximum.Actually ,the uptake of such UPR hampering drugs in cell kinds other than the ones that are ER stressed   pancreatic β cells would be harmful if Terminal UPR     as well as     apoptosis  are needed for tissue regeneration  along with cell turnover.However ,the proof from these  Clinical Trials point that  a definite window  for enhancing ,or minimal postpone ,the reduction of the remaining β cells function  other than insulin  therapy   by itself.The query  of if β cells function   can get enhanced  in Type 1 diabetes by repurposing  T2D drugs  remains  still for discussion. Nevertheless, the proof  from these Clinical Trials  studying glucagon like peptide 1(GLP1), as well as     GLP1 receptor  signalling point that this  might not be efficacious (NCT 01155284, NCTo2284009)[66].With the further studies  start to get insight at which  time β cells have maximum  proneness  to  ER stress  stimulated  functional reduction  as well as     Terminal UPR   at the different stages of T1D generation,it might be feasible  to utilize  these treatments off and on as well as     when required maximum ,that prevents the adverse actions that occur following daily delivery.

3.2. Injury – stimulated β cells Senescence:
Even non-lethal types of β cells impairment further aid in T1D generation.A kind of subpopulation of β cells in the late stage of prediabetic  NOD mouse ,in seroconverted asymptomatic donors  along with recent onset  as well as     fully  generated  human  T1D donors activate  a DNA –damage stimulated  senescent fate [67](figure 1 B). Senescence by definition is a kind of programmed  growth halt ,usually stimulated by  different kinds of unrepairable cellular Injury,   aging or oncogenic stimulation [68].Whereas Senescence  is typically thought  of as a single phenotype /state ,a lot of escalating literature validates the belief  the various kinds of Senescence based on cell kind,  stage of generation  , as well as     provoking stimuli[69-71],actions of physiology of the tissue[72,73].Conversely advantageous kinds of Senescence are utilized for a lot of necessary events ,like embryonic growth and patterning[69,74], tissue regeneration[71],wound healing[75] along with  tumor suppression[76].Hence, Senescence has been pointed  as  antagonistic pleiotropy  at the time of evolution(i.e where more than 1 trait controlled by a gene where 1 is beneficial in early phase of life while at the late stage is harmful)[77].The absence of a unique marker for Senescence in vivo  has seen to it that the correct phenotypic definition  of these cells in different  tissues very difficult.Hence a lot of independent markers  are essential to validate these  claims regards to Senescence[78].

The provocateurs of the early DNA –damage as well as      Senescence stimulation in β cells at the time of T1D have to be found as yet. However ,the findings  that β cells Senescence as well as      apoptosis both take place  at the time of pathogenesis of T1D in humans  as well as      mice  favours  the fact that both  represent damage-stimulated fates[79].The queries that need to be addressed are what influences certain β cells to seek terminal UPR     ,whereas rest stimulate  a damage-associated  Senescence program? At the transcriptional as well as      functional levels    β cells   are believed to be heterogenous [80-82], as well as      heterogeneity  takes place at a lot of level s in   T1D[14].Tackling the basic query  regarding heterogeneity in  β cell  fates  would be of a lot of significance  for  getting insight in the pathogenesis of   T1D. as well as

3.2B. Injury – stimulated β cells Senescence- Molecular Pathways:
Senescence- associated secretory phenotype (SASP)

With regards to T1D, damage stimulated β cells     Senescence display hallmarks of  constant DNA –damage response(DDR),that implicates Ser 139 phosphorylated histoneH2A.X (alias  gamma H2A.X)[67],that is classically stimulated via the master kinase ataxia telangiectasia mutated(ATM) along with  marks-double stranded breaks[83].The halt of growth secondary to senescence gets mediated in these cells  by the up regulation of the typical cyclin –based kinase inhibitors , cyclin –based kinase inhibitor1a(Cdkn1a,alias p21) as well as       Cdkn2a(that  encodes  p19^Arf as well as      p16^Ink4a )[67]. Stimulation of ATM  mostly signals  to stimulate Cdkn1  aexpression  through the the p53  tumor suppressor as well as       knock out  of Atm in β cells      ameliorates the DDR  which gets stimulated by the DNA –damaging  drug streptozotocin  [84] that validates  the preservation of this pathway in β cells.Noticeably ,  the kind of      β cells     Senescence in T1D is separate  from what gets seen  at the time of age associated β cells     Senescence[85], The Senescence as well as       T2D[86]. β cells that are aged   upregulate   p16^Ink4a  but not p21   as well as       don’t display proof of continuing   DNA –damage[67,85].The constant DDR of these β cells  that are    Senescent  in  T1D further discriminates  them from the β cells  that are    Senescent  in  T2D visualized in,  that simulates an exaggerated aging phenotype[30,86].Moreover it is noticeable that Senescence is not just limited to  β cells in T2D , along with the associated  metabolic syndrome ,but takes place in a lot of cells  that includes preadipocytes  as well as       hepatocytes’[87].Akin to that Senescence signature in NOD mice was further visualized  in human β cells in a small cohort  of seroconverted donors(single or double auto antibodies  positive)recent onset along with fully  Developed T1D donors (that spans <1yr to6yrs  disease existence[67].In T1D Senescence in  human  β cells  is seemingly associated  with  DNA –damage,as validated by  the finding  that Senescence markers akin to this  can get stimulated  in normal human islets in culture   with the DNA –damaging drug bleomycin [67].Noticeably ,a previous report further  illustrated the proof for stimulation of the DDR in β cells   of new onset T1D  donors (wks to a few mths  following diagnosis ),pointed in that study by foci of the factor for repair  namely p53 binding proteins 1(53 BP1[85).

Injury – stimulated β cells   that are Senescent generate 2 extra phenotypes, Specifically applicable to their harmful actions on the islet microenvironment as well as       T1D propagation.  Firstly, they particularly upregulate the antiapoptotic protein B Cell lymphoma(Bcl-2)[67](figure1B).The family members of   Bcl-2 are either pro or antiapoptotic,  that ensures a finely tuned regulation mode  over the  intrinsic apoptosis[88]. Upregulation of   the antiapoptotic  protein B Cell lymphoma family members that include  extra-large (Bcl-xL), B Cell lymphoma w(Bcl-w) as well as /or Bcl-2 appears to be a main hallmark  of maximum kinds of Senescence as well as        contributes to  a prosurvival phenotype  in Senescence as well as         cancer [88].Hence β cells   that are Senescent  can probably dodge  the external  clues from the environment,  that includes lymphocytes that are infiltrating  as well as       inflammatory   macrophages  that are resident which in other circumstances  would instigate    apoptosis.  This property in Specific sets, Injury – stimulated β cells   Senescence, besides in the form of totally separate fates in contrast to UPR - stimulated apoptosis, since   Senescenct  β cells     have a long life . Second Senescenct β cells     can stimulate a    pro inflammatory   secretome that is classical of other kinds of Senescenct cells   which was initially known as   Senescence- associated secretory phenotype (SASP) [67,89]. SASP is a relevance –based  as well as       dynamic program involving  secreted cytokines, chemokines, growth factors, shed   receptors, as well as       matrix proteases  which are markedly immunogenic  as well as       modulate paracrine signalling with the adjacent cells [68,70,90].The basic aim of SASP  in vivo appears to be immune surveillance  along with removal of Senescenct   cell from the tissue resulting in  resolving of inflammatory    responses[78,90]. Nevertheless,in relevance to TID ,SASP appears  to not get resolved  since Senescenct  β cells      keep on collecting  as the disease propagates[67]. Senescenct β cells       further possess escalated lysosomal β galactosidase activity [67],a phenotype that is shared by β cells    aging as well as        β cells   Senescence in T2D[85,86], known as   Senescence- associated β-gal activity[91].

Still one has to find out  regarding  how transition from Senescence  to SASP   in β cells     occurs,since just a subset of  Senescenct  β cells    generate   SASP markers, as well as        a lot of difference in the rate of SASP    β cells  in NOD mice as well as   human donors with T1D[67].Lastly it is significant to appreciate  whereas these collected    Senescenct  β cells    display changes in certain critical β cells     identity genes a(like reduced Ucn3)[67],they are separate from   β cells      which get totally de differentiated (like illustrating  endocrine  precursor marker Ngn3) or trans differentiated(like  displaying a bi hormonal  or poly hormonal phenotype).This type of conclusion gets validated  by the findings that  they sustain great amount of Ins1 as well as        Ins2 expression dependent on single-cell  RNA –seq as well as        have  what looks like normal amounts of insulin as seen by IHC[67].If the Senescenct  β cells      subpopulation  in NOD mice has an overlap with that subset  which fights the autoimmune  fight as well as        continues once fully developed diabetes in this model[92],has to be found ,despite the putative  antiapoptotic  phenotype  of the former  agrees with this thought.

4.Senescence Targeting Treatments in T1D-Chances of Clinical Translation:
With the use of pharmacological  agents , Senescenct  β cells     collection can get ameliorated ,resulting in a pause in the autoimmune event  as well as        avoidance of T1D in NOD mice.Inhibitors of Bcl-2 which act as senolytics(drugs clearing Senescenct   cells)agents  selectively    stimulate  in the apoptosis   in Senescenct  β cells(figure1B) without any change that can get picked up in the main lymphoid or myeloid cell kinds  in   T1D[67].Hence    treatment of islets that have been isolated from NOD mice or delivery of senolytics agents ABT-199 or ABT 737 to,prediabetic mice reduces the Senescencce as well as        SASP markers ex  vivo as well as        in vivo[67].Hence therapy  with ABT-199(alias Venetoclax) got recently approval from FDI  in the form of 1^st class Bcl-2 inhibitor  for combination therapies in chronic lymphoid leukemia  in which overexpression  of  Bcl-2 takes place.Akin to that ,suppression of  SASP pharmacologically in β cells  attained transcriptional inhibition of the bromodomain extraterminal domain(BET) protein family[93].At present small Molecule  BET inhibitor iBET[762,at present in phase I/II trials for different cancers[94],avoids  diabetes as well as        represses SASP in β cells  of NOD mice in vivo as well as        human islets ex vivo[93].A BET inhibitor  from the prior generation iBET-151 was also demonstrated to avoidT1D in NOD mice, as well as        pointed actions on both β cells   as well as        macrophages[95].In toto these observations point that besides BET inhibitors    suppress  SASP pharmacologically in β cells,they further reduce the BET     protein-modulated inflammatory pathways  in myeloid cells[96].However,proof from  studies  in NOD mice,human  pancreas  donor specimens  as well as        islet    culture  models validate the clinical utility in  of  β cells     Senescence  therapies  for avoidance of   T1D.It  still is not clear  if therapies   targeted at Senescence would be advantageous   following T1D initiation  or might be utilized  at the time of partial T1D remission  honeymoon phase.

For being successful to get therapies  that targeted Senescence in relevance to clinical   utility,some problems have to got to be overtaken.1)The present generation of Senescence targeting treatments  as well as  senolytics  are the ones that get repurposed from the oncology branch , as well as        whereas maximum possess adverse effects  that can be agreeable  in adults they have  not been  evaluated in children ,hence might cause a  lot of  risk.Open label small cohort phase1 Clinical Trials to delete therapeutically   Senescenct   cells in adult subjects with Diabetic Kidney Disease[97] or idiopathic  pulmonary fibrosis[98] have  utilized    a cocktail of  senolytics agents  Dastanib plus Quercetin(D+Q) that are delivered off and on, as well as        have illustrated   good safety  along with some effectiveness . Nevertheless, it is not known  if D+Q have the capacity of influencing the, Senescenct  β cells     collection that occurs in T1D.Secondly ,since these agents possess off target actions,  it would be essential to  generate targeted  administration methods  to maximize uptake  by  Senescenct  β cells     .  Whatever strategies that are coming up regarding therapeutic targeting of Senescenct   cells in other tissues [99] might aid in generating a similar  system  for      β cells.  3)Lastly theabsence of Clinical correlates  interferes with the  capacity of anticipation  which seroconverted  patients possess  the maximum burden of     Senescenct  β cells  as well as        thus would get maximum efficacy from these therapies .Actually it appears  that a broad difference  in the degree of  Senescenct  β cells       in islets of recent onset Type 1 diabetes as well as        seroconverted donors[67],that highlights the belief of heterogeneity of   β cells      fates .Procuring a Biomarker  for   Senescenct  β cells      would  lay open the stage of questioning  patient cohorts  to  generate  association  among Senescence along with other clinical features  to isolate patients  which might prove to be great  subjects for  β cells      Senescence  treatment[67].

5.1. Restof States of β cells impairment:Definite proinsulin processing as well as  Bihormonal  Beta/IsletCells:
A lot of proof  for other non-damaged impaired states in Beta   Cells has  got documented recently .These represent aberrations  in proinsulin processing   which has been proved in T1D[27,100,101], as well as   trans differentiation /changed identity in  recent onset as well as    generated Type 1 diabetes[102,103]. Proinsulin represents the precursor Molecule subsequent to deletion of the N-terminal signal peptide from pre proinsulin in the ER [104]. Prohormone convertase (PC )1 as well as 3 ,PC2    along with carboxypeptidase E(CPE)that represent neuroendocrine peptidases catalyze  stepwise  proteolytic cleavage processes  which finally develops mature insulin as well as         C peptide  for exocytosis[105].Noticable studies done by independent workers have illustrated  a proinsulin processing   impairment in generated Type 1 diabetes,as pointed by i) escalated proinsulin: insulin ratio in islets , as well as        ii)constant proinsulin liberation observed in serum of longstanding Type 1 diabetes subjects[27, 100,101], PCSK1 mRNA  (that  encodes  PC 1 as well as         3  isoforms  was reduced by  significant amount  in T1D pancreata ,while expression of PCSK2(that  encodes  PC 2) as well as         CPE were not influenced [101],pointing  that the aberration in proinsulin processing    occurs due to decrease in PC1 as well as     3 activity. One more study validated this observation  at the protein  level, with decreased PC1 as well as   3 found from T1D donor islets  as well as         a pattern towards reduction in CPE amounts [100].Further whereas INS mRNA  was plenty in  developed  T1D pancreata,  markedly low nascent transcript(alias heterogenous nuclear RNA ) was observed from  the INS promoter ,pointing  that transcription that was continuing gets impaired in T1D[101].Then the query comes out that what is the mode by which proinsulin processing    impairment starts in long time T1D,that remain significant queries for future.That would aid treatment strategies  to enhance proinsulin processing   as well as     probably insulin generation as well as         liberation in longstanding Type 1 diabetes subjects.If this stage of impaired proinsulin processing    is a characteristic that occurs along with UPR  as well as        /or  senescence in   β cells has to be unearthed.

Besides    proinsulin processing    impairment,a subset of β cells in  recent onset  along with longstanding T1D have  been illustrated to have a bi hormonal state with simultaneous generation of α cell hormone glucagon  along with insulin[102,103].This thought  that islet cells trans differentiate  in T1D was not corroborated  initially till Lam etal.[  29]stained pancreas specimens obtained  from a huge cohort of T1D donors  including children to older adults having differing disease time period (from new onset to fully developed ) for islet endocrine  markers  as well as         observed  no proof  of new    β cells generation(alias neogenesis) or bi hormonal islet cells[82]. Nevertheless, another study  that was published in the same time duration  isolated a highly  small sub population(2-5%) of islet  cells  in a small cohort of fully generated T1D,which were double positive for glucagon  as well as         insulin,but had absence of canonical alpha cell  markers that identify    α cell Aristaless related homeobox(ARX) as well as   DNA methyl transferase 1(DNMT1)[103]. Following that  a better  histochemical staining  strategy was generated  to isolate  markedly low  amount of insulin  expressing cells(insulin^low )in islets from recent onset  as well as          generated Type 1 diabetes donors ,that were pointed  to portray the histological correlate  towards the clinical  continuation of insulin liberation in micro amounts in case of longstanding T1D[102].Earlier work has pointed  that a subset of β cells become insulin negative islet cells might be   insulin^low ).

Noticably insulin^low  islet cells were isolated  in T1D donors of every age ,pointing that this phenotype  is not associated  with   disease  period , as well as          a subset of these cells   in recent onset as well as          generated T1D were demonstrated to coexpress  islet   α cells as well as  β cells  transcription factor homeobox protein NKX6.1  as well as          ARX respectively [102].If these are β cells   which have trans differented ,or α cells which had attained low amount insulin generation   along with β cells    identity markers,could not be found out. Nevertheless, other islet   endocrine cells    hormones were further documented in the insulin^low   cells,like somatostatin, ghrelin as well as      pancreatic polypeptide ,  pointing  that   insulin^low    cells are not   generating simply by islet   α cells into β cells inter conversion[102].Is it that these cells originate in the asymptomatic  stages ,playing an etiological part in T1D etiopathogenesis,or are they generating as a later result of  the metabolic actions of as well as suboptimal glycemic regulation?Extra studies are essential  to work out how the initiation of  insulin^low    cells in T1D  pancreata as well as          find out if insulin generation along with β cells    identity can get restored to these cells in T1D  subjects .

5.2. Extra modes of β cells impairment:
Various other modes might aid in different ways of β cells impairment,that is not well known ,that includes Viral infections,antiviral responxses as well as         impairment in autophagy  along with mitochondrial  function.  Whereas definitive proof for a viral  etiology  for T1D     has to get proved formally [17],a lot of studies have correlated      viral infections with     T1D[107].Actually a lot of GWAS loci remain in genes  possessing  antiviral activities  that modulate the innate  immune   signalling through  the  Type 1 interferon   pathway [108].  Antibody    modulated repression of the Type 1 interferon signalling avoids T1D in NOD mice [109], as well as treatments that target Type 1 interferon signalling are being utilized to fight a lot of systemic autoimmune diseases [110]. Hyperexpression   of  HLA Class I   takes place at the time of   pathogenesis of   T1D[111] as well as  ahas been    associated  with    Type 1 interferon  signalling in human Islet   as well as Endo C-β H1   β cells  models [112].Polymorphisms  in genes that encode innate  immune   as well as      antiviral   factors  keep a good balance among    efficacious host response  to Viral  pathogens  on one end as well as         the    autoimmunity precipating  on the other end[113]. Intriguingly, interferon signalling further facilitates expression of programmed cell death-1 ligand 1(PDL1) on β cells   in NOD mice as well as       humans [114], a critical immunoprotective factor on   β cells [115], hence further interventions to facilitate   β cells    survival might   utilize this pathway.

β cells     autophagy is one more significant mode essential for making sure survival occurs at times of stress in mice as well as       humans [116]. Impairment in autophagy  in β cells      of  T1D pancreas donors in relation to controls was   illustrated in a recent study [117].The other organelles of β cells     which might be dysfunctional  are mitochondria[118].A recent study  pointed no main mitochondrial   Ultrastructural changes  in β cells       in a small cohort of T1D donors   by electron microscopy(EM)[119],a new Large –scale  electron –microscopy(EM) database  for human Type 1 diabetes EM imaging data collection  from a much bigger sample of non-diabetics ,autoantibodhy positive  as well as       T1D donors   [120] would be of use for getting the answer for structural impairment in mitochondria of β cells       at the time of generation of T1D.

6.β cells treatment Combination with Immunotherapies for Type 1 diabetes Avoidance:

6.1Advantages as well as  limitations of Combination treatment strategy for T1D Avoidance:
The thought of Combination of β cells      treatment present currently with  Immunotherapies for Type 1 diabetes therapy  has got recently advised[35],since it seems to be a lucrative strategy for efficaciously tackling impairment o9n either side of the pathogenesis[121](fig2).This idea  might implicate treatments  which target  terminal UPR along with   Immunotherapies in Combination like CD3 antibodies,with the aim of escalation of β cells       survival as well as         reducing or reversing β cells   autoimmunity  at the time of window following   seroconversion as well as   early initiation of metabolic impairment(stage2).The more  inventions continue on subtle immune  as well as     metabolic alterations  which associate  with      propagation of seroconversion,the window in the natural history of   given a chance  for intervening  which could avoid  subsequent deterioration of  functional  mass of β cells  . ] (figure2).

Legend for Figure 2:Courtesy ref no-40-Combining beta cell therapy and immunotherapy for T1D prevention. There is a clear window for preventing T1D onset during stage 2, where seroconversion and dysglycemia are evident but patients are otherwise asymptomatic. The effectiveness of beta cell-targeted therapies, such as drugs inhibiting UPR or targeting senescence could be synergistic with immunotherapy during this stage. Intermittent use and more targeted delivery of these treatments during this preventive window could afford long-term prophylaxis against further loss of beta cell mass and function (green line), altering the typical trajectory of declining beta cell mass and function leading to T1D onset (red line).

Nevertheless,  the utilization of Combination  treatments would come with its own problems  in the clinical scenario.Every one of treatments  alone  possess a lot of side actions .Thus adding the therapies together  would markedly escalate the number of these processes in a particular patients cohort .It is feasible  that therapies administered more off as well as      on  along with  greater targeted treatments would ameliorate the adverse actions to certain degree .Furthermore β cells   treatments  could be delivered in an alternating method with     Immunotherapies,since there is no explanation to  point that delivering both forms of therapies  together would be  needed for ideal effectiveness .However ,a further challenge  of utilizing Combination  treatments in T1D  could arise from the nonpanticipation of the actions of 1  treatment   on the other cell type (like action of β cells   treatments   on the immune system.Like ER stress history of    UPR Inhibitor imatinib ,that appears  to partly postpone  deterioration of  functional   β cells in the new onset  T1D(NCT01781975) history of    spares β cells    to revert T1D in NOD mice[57], along with acting on ROS signalling in B cells ,a property  that is essential  for its treatment efficacy [62] .Anticipation as well as      disengaging the side actions that are not intended  regards to  β cells   treatments   on cells in the immune system could  thus become a main hindrance  for moving further  with proof dependent clinical trials  utilizing    Combination  treatments.

6.2B. Combination treatments as well as reanalysis of T1D Etiopathogenesis:   
Probably  as per context the potential of Combination  treatments is the earlier belief made beforehand  which looks at T1D being a single  uniform disease(even though implicates both immune  along with β cells  constituents).This belief is gradually getting abandoned  ,since escalating  knowledge regards to inter patients differences  in practically all  areas of the disease ranging from epidemiology    along with environmental triggers  to age of initiation .variations in sex ,degree of autoimmunity robustness , metabolic impairments as well as      insulin effectiveness [14,50].Present gaps in what we understand till now regarding T1D etiology  area the relative part played by β cells death  as well as      impairments  on one end , as well as      immune system impairments on the other end are some aspects in the field  where evaluators  are trying to critically analyze the earlier presumptions[36].Actually certain researchers in the field getting more serious as well as      asking for total reanalysis of T1D causation ,depending on the  basis of disease  endotypes,implicating  mainly immune vis a vis mainly β cells  stimulated pathogenesis[121-123].As per this ,already in the field it has been revealed other separate  ,albeit poorly grasped types of insulin deficiency –T1D[124],to the lack of β cells  auto immunity in idiopathic or nonimmune T1D[2].Certain place among the extreme ,that have characteristics of T1D as well as      T2D,is latent autoimmune Diabetes in Adults(LADA)[125],that presents much later in life  as well as      typical T1D[13]. LADA displays proof of β cells impairments as well as      /or deletion in the existence of mild autoimmune generation,that makes it essential  for alterations towards classical T1D regimens[126].

Despite still presumptive right now ,collecting both experimental as well as      clinical proof  in corroborating an endotypic framework in T1D  would aid  generation of personalized interventions  as well as      enhancing  the efficacy of the clinical trial designs[123].Having this insight ,it would then be feasible  to pick up the therapies that are most appropriate depending on the endotype  of the patients,that is a big leap  moving towards a personalized treatment strategy  that has been a long standing dream regarding this disease[123,127]. Nevertheless, despite proper division as per the endotype of the T1D ,early in the natural h/o disease (like at stage 2 ((figure2),in future a more particular strategy  of Clinical Trials utilizing  a single drug treatment(like β cells   or Immunotherapies)that is tailored for the particular   instead of trying to influence both β cells    as well as      immune system   utilizing Combination  treatments.Anyhow ,since Clinical Trials for treatments that are targeting β cells     in T1D are still in budding stage in contrast to    the large  numbers along with  history of   Immunotherapies trials [35,128],it is not possible  that β cells    treatment would get combined with Immunotherapies for avoidance of T1D in the coming future.

7.Conclusions as well as Further Guidance:
This concept that is getting generated of transferring the looking of T1D as just as an autoimmune disease   towards a heterogenous  disease of both the immune system along with islets,is a significant one  that has already aided in newer  treatment   chances  . β cells   UPR ,senescence ,proinsulin processing impairments as well as       identity alterations  are all  areas with robust chance for generation   of longtime avoidance strategies  for the ones at risk of T1D initiation .Actually these stages might be akin to the iceberg tip ,since there exists no explanation to point that no other types of  β cells impairments that has to be invented in T1D .  Further escalating recalling of      impairments in other islet cells like α cells [129] as well as       glucagon liberation exocrine atrophy along with pathophysiology[130],that might also yield  targets for therapy.

Cytokines play crucial roles in orchestrating complex multicellular interactions between pancreatic β cells and immune cells in the development of type 1 diabetes (T1D) and are thus potential immunotherapeutic targets for this disorder. Lu et al[131] detailed how Cytokines  can stimulate controlling functions—like , IL‐10, TGF‐β and IL‐33—are believed to restore immune tolerance and avoid β‐cell damage.As compared to , cytokines like IL‐6, IL‐17, IL‐21 and TNF, that facilitate the differentiation as well as       function of diabetogenic immune cells, are thought to lead to T1D onset and progression. However, targeting these impaired cytokine networks does not always result in consistent effects because anti‐inflammatory or proinflammatory functions of cytokines, responsible for β‐cell destruction, are context dependent. Thus, Lu et al ]131] comprehensively summarise the current knowledge on the involvement of well‐known cytokines in both the initiation and destruction phases of T1D, besides explaining the advances in recently discovered roles of cytokines. Additionally, they stressedthe complicated nature   as well as       involvement of cytokine modulation therapy and detailed the ways in which this strategy has been translated into clinical trials.

Increasing evidence highlights the role of the interleukin (IL)-17 family in pancreatic diseases. IL-17A induces acinar cell injury directly, recruits’ neutrophils, and cooperates with other inflammatory factors to exacerbate pancreatic inflammation. It also triggers islet β-cell apoptosis and nitric oxide-based cytotoxicity, hence exacerbating islet inflammation. IL-17A seems to have different roles in pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer (PC). IL-17A participates in the propagation of acinar-ductal metaplasia (ADM) and PanIN, but not associated with the features of PC stem cells and the overall survival of patients. Acting similar to IL-17A, IL-17B accelerates the invasion and metastasis of PC, and predicts prognosis of PC and the therapeutic effect of gemcitabine.Thus Clarke et al.[132] reviewed   the present  insight in  the pathogenesis of IL-17 in pancreatitis, type 1 diabetes mellitus (T1DM), and PC, as well as potential pharmacotherapy targeting IL-17 and its receptors in pancreatic diseases. The findings summarized in this article are of considerable significance for understanding the essential role of IL-17 in pancreatic diseasesas we had earlier discussed in the role of autoimmune diseases, like endometriosis,RA,SLEetc [133]

The etiology of this disease is complex and difficult to study due to a lack of disease-relevant tissues from pre-diabetic individuals. Yip etal.[134],studied along with  conducting  gene expression analysis on human pancreas tissues obtained from the Network of Pancreatic Organ Donors with Diabetes (nPOD), and demonstrated that 155 genes were differentially expressed by ≥2-fold in the pancreata of autoantibody-positive (AA+) at-risk individuals  in contrast to healthy controls. Only 48 of these genes remained changed by ≥2-fold in the pancreata of fully generatedT1D patients. Pathway analysis of these genes showed a significant correlation with different immune pathways. They   could   corroborate the differential expression of eight disease-relevant genes by QPCR analysis: A significant upregulation of CADM2, and downregulation of TRPM5, CRH, PDK4, ANGPL4, CLEC4D, RSG16, and FCGR2B was confirmed in the pancreata of AA+ individuals versus controls. Studies have already implicated FCGR2B in the pathogenesis of disease in non-obese diabetic (NOD) mice. Here they demonstrated that CADM2, TRPM5, PDK4, and ANGPL4 were changed akin to the pancreata of pre-diabetic 12-week-old NOD mice compared to NOD.B10 controls, pointing to a possible role for these genes in the pathogenesis of both T1D and NOD disease. The loss of the leukocyte-specific gene, FCGR2B, in the pancreata of AA+ individuals, is particularly interesting, as it may serve as a potential whole blood biomarker of disease progression. To test this, we quantified FCGR2B expression in peripheral blood samples of T1D patients, and AA+ and AA- first-degree relatives of T1D patients enrolled in the TrialNet Pathway to Prevention study. We showed that FCGR2B was significantly reduced in the peripheral blood of AA+ individuals compared to AA- controls. Together, these findings demonstrate that gene expression analysis of pancreatic tissue and peripheral blood samples can be used to identify disease-relevant genes and pathways and potential biomarkers of disease progression in T1D [134]

While many genes associated with the risk of diabetes have been identified to date, the mechanisms by which external triggers contribute to the genetic predisposition remain unclear. Here,Kirak et al.[135] derived embryonic stem (ES) cell lines from diabetes-prone non-obese diabetic (NOD) and healthy C57BL/6 (B6) mice. While overall pluripotency markers were indistinguishable between newly derived NOD and B6 ES cells, we discovered several differentially expressed genes that normally are not expressed in ES cells. Several genes that reside in previously identified insulin-dependent diabetics (Idd) genomic regions were up-regulated in NOD ES cells. Gene set enrichment analysis showed that different groups of genes associated with immune functions are differentially expressed in NOD. Transcriptomic analysis of NOD blastocysts validated several differentially overexpressed Idd genes compared to B6. Genome-wide mapping of active histone modifications using ChIP-Seq supports active expression as the promoters and enhancers of activated genes are also marked by active histone modifications. They further observed that NOD ES cells liberate greater inflammatory cytokines. Their data pointed that the known genetic predisposition of NOD to autoimmune diabetes leads to epigenetic instability of several Idd regions [135].

It is apparent that a lot of queries have to be tackled in this field.Namely the exact association  among these β cells impairment  states , as well as       what initiates β cells to a particular impairment  state in any particular islet along with patient? The ones that exist together or are mutually separate? The basic etiologies of every one of them, as well as        how it influences the disease pathogenesis in the clinically known stages? Would it be feasible to combine β cells treatment with each other for targeting various types of β cells impairments concurrently?  These remain the key queries  in this area  for tackling in future  if our insight  of β cells   /islet cells  impairment in T1D can get safely along with efficaciously  translated in clinical scenario.It is certain that our insight of T1D will keep on getting generated  as well as       get more refined with advances in experimental  technological equipment along with strategies ,like  high sensitivity immunohistochemistry [102],single cell phenotyping [81],image cytometry as well as       high throughput evaluation [28],ultrasensitive hormone assays [27] as well as       pancreas slice technology[50]. Nevertheless, propagation will be based on the agreement to challenge  the existing dogmas along with long term presumptions regarding T1D[32,122,123].On these bricks the assurance of treatments  with objectives of reverting β cells  function as well as       survival  for avoidance along with  treatment of T1D will ultimately get achieved.