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Epigenomics in Childhood-Onset Diabetes Therapy: A Critical Review

Kimiya Noor 

Emporia State University 

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​Kimiya Noor is a Biochemistry and Molecular Biology freshman at Emporia State University. She wrote the Boe Award-winning paper, entitled "Epigenomics in Childhood-Onset Diabetes Therapy: A Critical Review" with Dr. Gardner. Kimiya plans to pursue an MD-Ph.D with her empathy for serving the underprivileged and keen interest in biomedical technology.

Panpsychism: A Beautiful Circumvention

Science Lab

Abstract 

This review analyzes and summarizes the most recent scientific research papers regarding the effects of epigenetics on Type 1 Diabetes pathogenesis and treatment. It explores possible causes and environmental factors that play crucial roles in the tragic disease through epigenetic markers, including DNA methylation, microRNAs, and histone modifications. By compiling the great number of new emerging studies in this specific field, the review attempts to establish a clear connection between environmental triggers, the epigenetic modifications that follow, and the clinical benefits (diagnosis, progression markers, inhibitors, etc.) of them in juvenile diabetes. Non-epigenetic studies of this disease have not yet provided sufficient explanation for the unknown etiology and cure of this unpreventable disease, however, epigenomics can provide a novel understanding of this disease. Limitations and agreements between papers in this rapidly growing field of study are also carefully analyzed to explain further research required and how it validates and supplements research outside of epigenetics regarding Type 1 diabetes.

Introduction

Type 1 Diabetes Mellitus (T1DM) is a deeply-researched and well-defined chronic autoimmune metabolic disease, most common in children and adolescents, characterized by hyperglycemia [24, 40]. As of 2021, there are > 9 million individuals globally living with this chronic disease across all ages, 18% of which are younger than 20 years old [39, 40]. Since the 20th century, T1DM incidence (new cases) has been on a constant global rise, estimated to be increasing by 3% per year [41]. However, there have been reductions in the mortality rate [40]. Multiple known and some unclear factors are hypothesized to be responsible for this rise [41], which will be discussed more in-depth later in this paper. There is an urgent need for T1DM data by age from countries in order to improve T1DM research, treatment, and to avoid premature T1D mortality [42]. A study in 2022 predicted a staggering increase to 13.5-17.4 million prevalent T1DM cases in 2040 with their T1D index model [39], which would double the global burden of T1D and have various negative implications on healthcare systems worldwide. The growing prevalence calls for a rise in the standard of care (eg. insulin delivery, advocacy, allotment of resources, lesser misdiagnosis, etc.), better diagnostic understanding of T1D, and improvements in research [42].

T1DM is a very difficult and expensive condition to manage for survival. It is an incurable, lifelong disease affecting people from young ages to adults. Positive outcomes require constant management; spanning from daily exogenous insulin injections, to constant self-monitoring of blood glucose levels, check-ups, etc. [40]. After all, 3.9 million T1D deaths could have been avoided via sufficient diagnosis and ongoing care [45]. The disease extends to ages beyond youth and can lead to complications like cardiovascular complications, neurological complications, diabetic retinopathy, diabetic foot, kidney damage, etc. [43, 44]. The prevention of a few of these complications through epigenetics will also be touched on later. This paper will explore diagnostic methods and recent potential treatments for this alarming disease through epigenetics.

Cellular Processes / Immunological Mechanisms Leading up to Pathogenesis of T1DM

            T1DM is also known as insulin-dependent diabetes. It is the condition whereby the beta cells in the pancreatic islet of Langerhans are destroyed by the immune response of T lymphocyte cells. Beta cells are responsible for secreting insulin, a hormone that is responsible for metabolizing sugar and regulating glucose levels in the blood [46,47,48]. There is then an irreversible loss/decrease of endogenous insulin production and hence exogenous insulin-replacement therapy is needed. Beta cell autoimmunity in T1D is often marked by the appearance of four autoantibodies against certain beta cell proteins: islet cell antibodies (found in 70% T1D patients, correlated with age), glutamic acid decarboxylase 65-kilodalton isoform antibodies (GAD-65) —found in 80% T1D patients—, insulin autoantibodies (IAA) (found in 69-90%) and insulinoma associated-2 autoantibodies (IA-2A) (54-75%) [75].

            In T1DM, antigen-presenting cells (dendritic cells) present beta cell antigens (foreign substance) to the immune system (autoreactive T Cells), and proinflammatory responses follow due to inefficient regulation of immunological reactions. Beta cell destruction requires cooperation between dendritic cells, macrophages, cytotoxic CD4+ and CD8+ T cells, B lymphocyte cells, chemokines, cytokines (pro-inflammatory mediators), and natural killer cells [8, 24]. Why this reaction is triggered is being constantly researched.

Genome-wide association studies revealed more than 60 loci associated with T1DM risk, and HLA (human leukocyte antigen) class II alleles are responsible for 30%-50% of genetic T1DM risk [49]. Non-HLA loci like variable number tandem repeats (VNTR) in INS (insulin) genes, mutations in the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) gene, FOXP3 genes, GAD2, and PTPN contribute to T1DM but with lesser effects. The triggering of these T1DM predisposing genes can be explained by DNA methylation, miRNAs, and histone modifications.

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Figure 1. Establishing Correlation between environmental Factors and Pathogenesis of T1DM. Processes leading up to the onset of T1DM.

Epigenetics in Human Autoimmune Diseases

Current knowledge has elucidated most aspects of T1DM but the exact causes leading up to this autoimmune disease and prevention are yet to be uncovered. Epigenetics, a budding field in genetics, are mitotically heritable and reversible changes that control gene expression and phenotype without altering the DNA sequence [54]. Epigenetic “tags” like DNA methylation and histone modifications (chromatin remodeling) change gene transcription (how DNA is read) in targeted cells and tissues in response to environmental triggers while working with non-coding RNAs [32, 51].

Started about two decades ago, studies aim to provide connections between environmental factors that possibly trigger the molecular pathways responsible for T1DM pathogenesis. The Environmental Determinants of Diabetes in the Young (TEDDY) study is a large-scale, ongoing study that researches the causes of T1DM since not all children with high-risk genes of T1DM go on to develop the disease [53]. Environmental triggers like infections, dietary factors, and others will lead to a better understanding of the etiology of T1DM which can help develop methods to prevent, delay, and reverse the disease. The TEDDY study is a dedicated and good resource to learn more about this topic.

While T1DM has a strong genetic component of around 80%, there are several characteristics of T1DM which establish the involvement of non-genetic or environmental factors in triggering risk genes. Firstly, there is only a 40% concordance rate of T1DM development between monozygotic twins [14] with exact genotypes, and 85% of T1DM individuals do not have a family history of the disease. The sharp increase in T1DM prevalence in the past century cannot be explained by changes in genetics and Mendelian inheritance only [55]. HLA haplotype (genes most responsible for T1DM development) does not determine T1D risk alone, epigenetic factors, like age, accelerate disease progression instead [55]. A Finnish study (the nation with the highest T1DM incidence) predicted, with the use of a model, that 88% of the phenotypic variance between T1D twin pairs is a result of genetic factors (influenced by epigenetics) and the remaining variance is due to unshared environmental factors [57]. The discussion below provides more detailed insight into the observations seen from the patterns of the three epigenetic variations in T1DM patients but there is much ambiguity as to how specific environmental triggers directly set off the modifications and their interactions.

In autoimmune disorders like Lupus, Multiple Sclerosis, Rheumatoid Arthritis, and T1DM, epigenetic modifications serve as regulators for complex biological processes, immune cell functions, and metabolic memory to modify the development of innate and adaptive immunity [14, 56]. Environmental influences dysregulate epigenetic homeostasis which has been found repeatedly to regulate the expression of immune system-related genes and cause loss of tolerance [54].

Table 1. Overview of the Genes/sites affected by the respective modification, the molecular effects, and the clinical potential for T1DM.

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DNA Methylation in T1DM Susceptibility genes

DNA Methylation is a critical epigenetic marker involved in the pathogenesis of T1DM. DNA Methylation is an epigenetic mechanism associated with promoting heterochromatin formation which regulates gene silencing, controlling gene imprinting and transcription levels, inactivating X chromosomes, and embryonic development [10]. DNA methylation is a heritable process whereby a methyl group (CH₃) is typically covalently added to the C5 carbon in the cytosine base by DNA methyltransferase enzymes (DNMTs) at the CpG (cytosine-guanine dinucleotides) site of a gene [11].

In T1DM specifically, a study done by Rakyan et al. among T1D discordant monozygotic (MZ) twins, with Illumina27K array, identified 132 different such CpG sites in T1D-relevant immune effector cells CD14+ monocytes. These sites correlated with the disease and are named T1D–associated methylation variable positions (T1D–MVPs) [6]. 58 of these CpG sites were hypermethylated and 74 were hypomethylated in T1D-affected individuals. The study established that MZ twins, genetically identical individuals, have epigenetic variation in terms of T1D-MVPs which could serve as a possible answer to the unknown etiology of the disease. However, more research with a larger sample size needs to be conducted to conclude the biological origins of such epigenetic variation which some hypothesize to be stochastic / environmental factors in utero. Besides just etiology, the T1D-MVPs could serve as a prediction for the disease like autoantibodies earlier than clinical diagnosis, albeit not accurately since not all T1D-MVPs result in the development of the disease [6]. Another similar study performed with HumanMethylation27 BeadChip identified 88 CpG sites (33 hypomethylated, 55 hypermethylated) of the lymphocyte cell among discordant MZ twins [12]. It concluded abnormalities in DNA Methylation patterns in T1D-associated genes such as the HLA (human leukocyte antigen), INS, IL-2RB, and CD226 in certain CpG islands. For example, genes HLA-DOB, HLA-DQA2, INS, CD226, and IL-2RB had hypermethylated CpG sites while HLA-E had hypomethylated CpG sites. The hypermethylated sites were involved in the defense and immune responses of the body while the hypomethylated sites were mostly involved in cell signaling and gene silencing in promoter regions [13]. Rui et. al. also provided concrete data that showed pro-inflammatory cytokines trigger epigenetic methylation of insulin DNA and progress T1DM [18].

These results were consistent with previous studies that identified the MHC regions (interchangeable with HLA) locus as the strongest contributors (responsible for 50% of the genetic risk of T1DM etiology [38]) [6, 11,14]. The INS locus is the second most important region in T1D pathogenesis risk. A supplementing study to Rakyan et al’s using more advanced methods found a negative correlation in insulin gene expression [17] with the hypomethylation of INS at CpG-19, CpG-135, CpG-234 and hypermethylation at CpG-180 in T1D patients [15]. All these are consistent, compelling indicators that DNA Methylation levels in specific T1D susceptibility genes are environment-gene interactions responsible for the pathogenesis of the disease [1, 15]. A recent study also confirmed distinct methylation profiles in CpG sites of CD4+ T cells and CD8+ T Cells in children developing beta autoimmunity [5]. There is however an increased need for research to pinpoint the time and cause of the origin and functionality of such epigenetic variations [15]. Likewise, a study in 2022 profiling HLA-identical families found hypermethylation at ICA1 (involved in insulin transport) and DRAM1 (controls insulin signaling and glycemic balance) autoantibodies of insulin-dependent diabetes [16].

Post Translational Modifications of Histone Proteins

Histone proteins neutralize negative charges of DNA by forming nucleosome complexes which allow DNA to pack tightly into structured chromatins. Post-translational modifications of the N-terminal amino acid of histones extruding from nucleosomes are constantly occurring and the processes have a myriad of effects on gene expression, levels of activation/inactivation of transcription, chromosome compaction, changing chromatin structure, DNA damage, and DNA repair [30, 31]. Histone modifications control the conversion of euchromatin (open chromatin, favorable to transcription, more access to embedded genes [1]) to heterochromatin (closed chromatin favorable to transcriptional repression) and vice versa [35, 36]. These modifications are carried out by enzymes classified into writers (modifies nucleotide bases and amino acid residues on histones eg. histone acetyltransferase (HATs)), erasers (enzymes removing modification done by writers e.g. histone deacetylase (HDACs) & histone demethylases (HKDMs)), and readers (involved in recognizing the above epigenetic marks) [36]. Some modifications on the N-terminal of histone residues include phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, and GlcNAcylation (eg. adding methyl groups on arginine or lysine residues via HMTs) [37].

In T1DM specifically, histone modifications contribute to diabetes progression through inflammation, vascular complications, and metabolic memory (long-term beneficial effects of hyperglycemia treatment) of T1DM. A pioneering study using chromatin immunoprecipitation assays profiled certain histone methylation/acetylation patterns in blood monocytes and lymphocytes of T1DM patients [33]. It was found that T1D patients had a much higher number of upstream regions of HLA-DRB1 and HLA-DQB1 enriched with acetylation of lysine-9 on histone H3 protein (H3K9Ac) compared to control groups. However, the study found there was no significant difference in the average number of enriched regions with lymphocyte H3K9me2 (demethylation of lysine 27 on histone H3 protein) between T1DM-affected and unaffected individuals [33]. However, a previous study showed increased promoter H3K9me2 in the CTLA4 gene (a T1D susceptibility gene) in T1D which was associated with autoimmune and inflammation-related pathways [59]. However, histone acetylation may also be protective against the development of cardiovascular complications [51].

Another newly discovered method relating acetylation on lysine-residue found on histone (especially isomeric histones with permutated PTMs) to phenotypic expressions in humans is using Bruker TIMS/ToF platform along with collision-induced dissociation in tandem mass spec. This method is in fact a superior method as it separates these isomeric histones without breaking them- allowing researchers to relate PTM connectivity information to phenotypic expressions; information that is lost when using current bottom-up and middle-down methods to separate histones [77].

Noncoding-RNAs

Non-coding RNAs (ncRNAs) play a vital role in T1DM epigenetic regulations and their functions are an intensively researched, but recently discovered area of study [19, 21]. Non-coding RNAs are a large portion of RNA molecules that do not code for functional proteins and hence their transcripts do not undergo translation [22]. Researchers speculate these non-protein-coding RNAs play a role in regulating other prominent biological functions such as homeostasis, disease pathogenesis, gene expression, and disease diagnosis [23]. Although, there is contention among the scientific community as to how many of such ncRNAs are actually useful in said roles [21]. There are two types of regulatory ncRNAs found to be relevant to T1DM (beta cell regulation) and other autoimmune disorders: microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) [2, 20].

miRNAs typically bind to the 3’ or 5’ untranslated region, coding sequence, or gene promoters of target messenger RNAs (mRNAs) to degrade it and inhibit protein translation [24, 25, 26]. miRNAs are found in solid tissues and cells, can predict the destruction or regeneration of endogenous residual beta-cell function, and are responsible for cell differentiation, proliferation, and apoptosis [20]. Under normal conditions, miRNAs play a crucial role in pancreatic beta cell function (insulin biosynthesis, insulin exocytosis, beta cell expansion) and hence carry clinical T1DM significance [24, 27]. The first quantitative study that analyzed serum samples of newly diagnosed T1D children for miRNA levels [20] found, in agreement with other studies, [24] that differentially expressed miR-181a, miR-24, miR-25, miR-210 and miR-26a are involved in beta cell apoptosis while miR-24, miR-148a, miR-200a, and miR-29a are involved in beta cell regulatory networks. Examples from other studies regarding the endocrine-pancreatic pathway include overexpression of miR-21 (regulates caspase levels) disrupting beta cell development, overexpression of miR-29 impairing insulin secretion, overexpression of miR-181, miR-7 and miR-124 dysfunctioning pancreatic beta cells. In immune system equilibrium, miR-34a overexpression negatively correlates with the Foxp1 gene and reduces B lymphocyte capacity. miR-23, miR-98, and miR-590 overexpression promote CD8+ T Cells that negatively target islet antigens, etc. [20, 24]. miR-25 is tissue-specific and notably promoted positive glycaemic control and improved residual beta cell function, making them potential intervention targets and useful biomarkers [20].

Using similar methods, another follow-up study, albeit with a limited sample of participants, proved the relevance of miRNAs on T1DM progression and its immunological pathways by identifying changes in levels of expression in different points of time of 8 miRNAs (hsa-miR-10b-5p, hsa-miR-17-5p, hsa-miR-30e-5p, hsa-miR-93-5p, hsa-miR-99a-5p, hsa-miR-125b-5p, hsa-miR-423-3p, and hsa-miR-497-5p) associated with pancreatic autoantibodies ICA, IA-2A, GADA65 and cytokines IL-4, IL-10, IL-21 and IL-22 [24].  Inflammatory cytokines induce miR-375 [1] miR21-5p, miR-30b-3p, miR-34, miR-101a, and miR-146a-5p in pancreatic islets, resulting in cytokine-mediated beta-cell destruction [58]. All this shows the involvement of miRNAs in T1DM.

The roles of the three modifications in the prevention and reversal of T1DM pathogenesis and further complications, their interactions with the environment (eg. diet), and their potential as therapeutic targets (targeted with biosynthetic inhibitors, enzymes, molecules, etc.) are discussed below.

Possible Environmental Triggers of T1DM and links to the respective Epigenetic Modifications

            As established earlier, even though there is a plethora of information regarding the strong genetic component and alteration of DNA sequence in T1DM, it is not the sole contributor to the susceptibility of T1DM [46]. 85% of T1DM patients lack a family history of T1DM and are not concordant between MZ twins with identical genes [49]. However, the specific mechanisms of how environmental stimuli make epigenetic marks on genes triggering beta cell autoimmunity are vague [46, 47]. This led to many hypotheses of the possible environmental factors and how they target the epigenetics of T1DM, discussed below. Understanding such environmental triggers on epigenetics can help formulate diets and lifestyles to slow-down the progression of T1DM and reverse it [1].

A study in 2022 done with breeding NOD (non-obese diabetic) mice proved that maternal and perinatal exposure to gluten-free diets reduced the development of type 1 diabetes by reducing autoimmune responses [50], and that the preventive effect is inheritable to the second filial generation. Surprisingly, the anti-diabetic immune response in the pancreas following a gluten-free diet is not dependent on gut microbiota diversity, but rather the early-life changes in an evolving immune system. Furthermore, a gluten-free diet with microbiota diversity reduced inflammation of salivary glands that improved the function of beta cells that are glucose-challenged [50]. Similarly, a study showed that gluten induces T-cell activation and intestinal inflammation [47]. However, there are disagreements as to whether the late introduction of gluten still has an effect on islet autoimmunity and T1D progression [51].

The non-genetic factors are hard to identify and an avenue of contention among studies. The impact of maternal and early nutrition on T1DM pathogenesis is a consistent area of study. Although some correlations are not concrete and conflicting, there is some evidence that early bovine milk exposure, early fruit introduction, virus/toxins exposure, and prenatal antibiotic use are diabetogenic factors [41,51,38]. Conversely, some T1DM protective factors include early breastfeeding, anti-inflammatory vitamin D exposure, certain pathogens, and probiotics [38, 41, 52].

Summarized from an abundance of literature, Figure 2 illustrates the well-researched and known environmental factors inducing negative T1DM triggers and protective factors.  To get more conclusive evidence, it is imperative to carry out large-scale studies. Some very recent ongoing TEDDY studies in 2022 include investigating the association between physical activity and rising hemoglobin A1c in oral glucose tolerance tests, HbA1c as time predictive biomarkers, celiac disease and gastrointestinal fungi relation with T1D risk, etc. One study found that maternal obesity before pregnancy and gestational weight gain of more than 15 kg significantly increased the risk of islet autoimmunity in offspring with high genetic susceptibility for type 1 diabetes, independent of maternal T1D [60]. Although this risk factor is supported by another study in 2018 [61], more high-quality studies need to be done to prove a definite causation. Maternal restriction of methyl-donating compounds like folate (lack of fruits) may result in T1DM in offspring [1] and folate cycle treatment can reprogram epigenetic expression in diabetic individuals and increase glycemic control [76].

Kohil et. al. evaluated in depth various diets and their triggering of exact epigenetic modifications [51]. The study details the cellular effects of specific diets on T1DM-associated genes and the following DNA methylation, miRNA expression, and Histone modifications.

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Figure 2. Possible Environmental Triggers of Epigenetic Modifications and their Effects on T1DM including diet and exposure to certain infections. Evaluated on the graph in order of reliability [32, 38, 41, 47, 51, 52, 62, 63, 64, 65, 66].

Evaluating Prospects/ Perspectives of Epigenetics in Treatment and Prevention of T1DM (Clinical Potentials)

Epigenetic mechanisms regulate gene expression, which influences the cellular processes in the various stages of T1DM and hence could serve as biomarkers for T1D onset prediction, disease progression, and drug delivery effect. Furthermore, Epidrugs target the reversible nature of epigenetic markers in genes for T1DM treatment [2, 63]. Some current emerging treatments include glucagon therapy, stem cell therapy, and islet transplantation.

Biomarkers for early detection and disease progression

As discussed in-depth in earlier sections, there are certain observable patterns among the epigenetic changes that are found in most T1DM-affected individuals. For example, genome-wide DNA methylation analysis found associated T1D-MVPs in the CD14+ monocytes of the affected MZ twin compared to the other twin [6]. The current method to clinically detect T1DM progression in youth is by monitoring the appearance and number of the islet autoantibodies against pancreatic beta-cell antigens, by which point, is too late for prevention as there is active islet autoimmunity [20] (at the time of diagnosis, a child has lost around  80–90% of the insulin-producing beta-cell function/mass [48]). As most studies agree, detecting earlier biomarkers like miRNAs, T1D-MVPs, and Histone modification patterns is critical in providing a larger window of time for intervention [1, 2, 4, 6, 20]. miRNA biomarkers can also evaluate the changes from T1D therapies designed to preserve/regenerate beta cell function. The stable and evolutionarily conserved nature of miRNAs makes them detectable in real-time with current technologies (PCR) with high sensitivity and specificity [20, 27]. The upregulated accumulation of certain circulating miRNAs and their role in T1D pathogenesis make them viable biomarkers for early preclinical T1DM disease and macro/microvascular complication diagnosis and assessment of disease progression.

Tested Epidrugs for T1DM

            Epidrugs is a fairly novel concept, aimed to reverse epigenetic marks that are associated with T1DM [67], some of which are stated earlier, to treat, prevent, and improve T1DM. Usually, they are enzymes that mediate epigenetic modifications by acting as inhibitors or activators of T1DM-associated proteins. Examples include HDACs, HATs, DNA methyltransferase (DNMTs), and miRNAs. Histone modifications and DNA methylation are very connected, both having strong effects on phenotype, as histone modifications contribute to the methylation of CpG sites [68].

Particularly, HDAC inhibitors (HDACi) targeting HDAC1 and -3 like licensed lysine deacetylase inhibitors vorinostat and givinostat, have shown promising results in reversing diabetes in NOD mice by protecting them from beta cell apoptosis resulting from inflammatory cytokines [68]. Inferring from successful NOD mice trials, similar studies have shown histone modification patterns in T1DM targeted by valproic acid, HDAC inhibitor trichostatin A (TSA role in ameliorating T1D supported by a 2022 study with NOD mice [3]), suberoylanilide hydroxy acid, sodium butyrate, metformin, resveratrol, and fenofibrate [63, 68]. In 2022, a study showed L-Methionine recovered the decrease in H3K27me3 and increase in H3K4me3 (histone modifications) in type 1 diabetic rats by modulating alpha-cell identity marker, beta-cell identity marker, and regulation of FOXO1 gene through histone modifications [54, 73]. These improved beta cell function and insulin signaling. DNA demethylating agents, like 5-Aza-2′deoxycytydine (DAC), induced demethylation of Foxp3 (transcripts Treg cells) gene which improved diabetes in cyclophosphamide-potentiated NOD mice [63]. The role of Sirtuin 1, a NAD-dependent deacetylase, also improved insulin sensitivity, though more study is required to tie to T1DM [63, 68]. A recent study showed hypomethylation of defected epigenetic sites in T-cells by the BCG vaccine was also seen to have a therapeutic effect on T1DM [74]. Intense research with a hopeful outlook has been going on for miRNAs in T1DM therapy [71] and Akil et. al [71] explains it in greater detail. The potential for miRNAs in T1DM is seen from how a single miRNA targets many genes sharing the same pathway [1]. Epigenetic drug I-BET151 reduced T-cells and reversed islet inflammation. According to Tajudeen et. al, epigenetic drugs can potentially be manufactured to neutralize cytokines, and block T cell interaction and antigen-presenting cells [1].

Epigenetic mechanisms in preventing Late complications of T1DM

            Current clinical treatment of hyperglycemia from T1DM is exogenous insulin-replacement therapy, although most T1D patients do not achieve glycaemic targets, which risks long-term diabetes complications in the patients [72] and hence epigenetic therapies can prove to be useful. HDAC3 plays an important role in the progression of type 1 diabetes to diabetic cardiomyopathy and hence inhibiting that enzyme with known HDAC3 inhibitor RGFP966 prevented the complication of T1DM [1]. Some natural HDAC/HAT inhibitors like sulforaphane (in broccoli sprouts) and diallyl disulfide (in garlic) have been shown to ameliorate T1DM complications like renal fibrosis [69]. HDAC inhibitors may also prevent the development of fibrosis in Diabetic Kidney disease though more research is needed since HDACi have broad substrate specificity [34]. HAT inhibitors like C66, a curcumin analog, also prevented diabetic nephropathy in mice [63, 70]. When tested in diabetic (type 1 and 2) patients, long-term cardiovascular complications of T1DM have been ameliorated with DNMT regulators metformin and inhibitor procainamide [71]. The strategies described above can supplement T1D treatments outside of epigenetics like stem cell therapy and insulin replacement therapy. 

Table 2. Evaluating Current/potential epigenetics-based treatment for T1DM, their Biological Model, Effects, and further research required. 

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Conclusion

T1DM is a multifactorial and complex disease that still requires intense research to truly understand its mechanisms. As epigenomics is still a fairly new and ever-changing conceptual field, it is essential in understanding and applying it to autoimmune diseases, and this paper aimed to show its vast potential in Type 1 diabetes treatment. There is credible evidence that certain epigenetic markers are found in notable amounts in T1D patients, indicating association. Hence, there is a necessity to replicate studies on larger scales and a clearer need to understand the precise respective cellular mechanism. Epigenetic modifications for certain gene expressions are reversible changes and could revolutionize the fate of young type 1 diabetes patients. Hence any research in this promising field is valuable while T1DM and autoimmune disease incidence is increasing. However, the large amount of newly emerging literature will require a level of discernment and understanding of the topic. Understanding levels of certain epigenetic modifications can help explain mechanisms of, predict, diagnose, track progression, treat and even reverse T1DM.

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