Pancreatic islet TFs are among the most important regulators of $\beta$-cell development, survival, and function because they regulate insulin gene expression. PDX1 is the major transcription factor (TF) that commits pancreatic progenitors to the insulin-producing $\beta$-cell lineage, thus providing functional identity to the cells [19, 23]. PDX1 positively interacts with its expression, activating the transcription of critical $\beta$-cell-specific genes, including insulin. Similarly, MAFA plays a vital role in glucose sensing within $\beta$-cells by modulating calcium signalling to amplify the response to glucose stimuli, an essential event for efficient insulin release [19, 24]. Moreover, MAFA can preserve $\beta$-cell identity and function, thereby maintaining optimal performance against metabolic stress. NEUROD1 also promotes $\beta$-cell terminal differentiation by inducing TFs such as PDX1 [17, 19]. This cooperative interaction increases insulin production and the formation of storage granules, resulting in functional maturation of $\beta$-cells.

Dysregulation of the action of the TFs NKX6.1 and the regulatory factor X (RFX) family is highly implicated in diabetes pathogenesis. NKX6.1 maintains $\beta$-cell identity and controls genes required for cell cycle progression, supporting $\beta$-cell proliferation and insulin gene expression [25]. Mutations in these mechanisms lead to aberrant glucose metabolism and insulin secretion. Conversely, Harris et al. (2021) [26] indicated that the RFX family of TFs, notably RFX3, RFX4, and RFX7, have been implicated in the development of cilia and central nervous system functions. However, they are also involved in glucose homeostasis. Their dysregulation can interfere with cell signalling pathways and reduce insulin secretion [25]. NKX6.1 and RFX factors are both critical in $\beta$-cell-cell function, with NKX6.1 playing a central role mainly in proliferation and RFX factors in insulin secretion.

Specific TFs control insulin biosynthesis and secretion at both levels. For example, Hasnain et al. (2014) [17] showed that interleukin (IL)-22 could rejuvenate glucose-induced insulin secretion by inhibiting endoplasmic reticulum stress caused by proinflammatory cytokines. This illustrates how TFs maintain $\beta$-cell function through complex, yet distinct pathways, each in response to a particular physiological setting of proliferation or secretion, a schematic representation of the sequential contribution of TFs to $\beta$-cell differentiation is shown in Fig. 2 (Ref. [17, 19, 25, 27, 28, 29]).

Fig. 2.

Schematic representation of how various TFs sequentially contribute to the $\beta$-cell differentiation pathway from early gastrointestinal endoderm to mature $\beta$-cells. The TFs forkhead box A2 (FoxA2), GATA binding protein 4 (Gata4), Pdx1, and SRY-box transcription factor 9 (Sox9) initiate general differentiation programs at early stages [19, 27]. When the pancreatic endoderm develops, Pdx1, NK6 homeobox 1 (Nkx6.1), hairy and enhancer of split 1 (Hes1), Sox9, pancreas transcription factor 1 subunit alpha (Ptf1a), and NK2 homeobox 2 (Nkx2.2) [25, 28]. Specification of the endocrine lineage involves TFs including, but not limited to, neurogenin 3 (Ngn3), Pdx1, Nkx6.1, Hes1, and FoxA2 [29]. Early endocrine progenitors would later express Ngn3, neurogenic differentiation 1 (NeuroD1), paired box 4 (Pax4), and aristaless-related homeobox (Arx) for endocrine commitment [17, 19]. NeuroD1, MafA, Pdx1, and Hes1 regulate immature $\beta$ cells. Maintenance of mature $\beta$-cell function and insulin secretion depends on other factors, including MafA, Nkx6.1, Pdx1, FoxA2, Klf11, and v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog B (MafB) [17, 29]. Thus, all of these TFs act in concert to develop and maintain functional $\beta$-cells in glucose homeostasis Created in BioRender.com. Simpson, A. (2025) https://BioRender.com/d30c608.

TFs in insulin-responsive tissues, such as the liver, skeletal muscle, and adipose tissue, are critical for maintaining glucose and lipid homeostasis. Dysfunctional activity seriously underlies the development of insulin resistance and T2D [30].

FOXO1 is an essential modifier of hepatic glucose metabolism that mediates gluconeogenesis in response to metabolic and carbohydrate signalling. Stojchevski et al. (2024) [31] demonstrated that in a model of induced insulin resistance, increased FOXO1 activity leads to higher hepatic glucose output through the upregulation of gluconeogenic genes, thereby exacerbating hyperglycaemia. More importantly, the interaction of FOXO1 with a key insulin signalling component, insulin receptor substrate 2 (IRS2), further supports the role of FOXO1 in perpetuating insulin resistance and disturbing glucose metabolism during chronic states [22, 32].

Peroxisome proliferator-activated receptor gamma (PPAR$\gamma$) is responsible for lipid metabolic pathways and insulin sensitisation [31]. It promotes the differentiation of preadipocytes into adipocytes, enhances the accumulation of stored lipids, and increases fatty acid uptake. By further modulating the insulin signalling pathway, PPAR$\gamma$ regulates glucose homeostasis and metabolic responses in white adipose tissue; thus, PPAR$\gamma$ regulates lipid storage and general metabolic health [10, 31].

SREBP1c, through Akt signalling, is an effective inducer of lipogenic genes in the insulin response, which requires nuclear trafficking in the endoplasmic reticulum followed by proteolytic processing for nuclear translocation to activate target gene expression [33, 34]. In insulin-resistant states, however, where this is impaired, apart from disturbing glucose homeostasis, SREBP1c unleashes uncontrolled lipogenesis, leading to hyperglycaemia, hyperlipidaemia, and hepatic steatosis. Insulin resistance is characterised by metabolic dysfunction and further drives the development of diabetes.

Carbohydrate-responsive element-binding protein (ChREBP) is a glucose-responsive transcription factor that interacts specifically with carbohydrate response elements, which mediate the primary transcriptional activity of genes encoding glycolytic enzymes in response to high glucose availability [33]. This transcription factor induces glycolytic and lipogenic genes in response to a high intake of carbohydrates in the liver, including liver pyruvate kinase (LPK), which is required for the appropriate use of glucose and deposition of triglycerides [33, 35]. The state of its phosphorylation controls its activity, that is, its DNA-binding ability and subsequent transcriptional activity. This marks the final role attributed to TFs, such as ChREBP, in maintaining blood glucose levels.

These interactions in insulin-responsive tissues are integrated into complex networks that regulate glucose and lipid metabolisms. For example, insulin, through Akt, activates SREBP1c but inhibits FOXO1 in the liver, and this reciprocal regulation maintains the balance between glucose production and lipogenesis [32, 35]. Insulin signalling in skeletal muscle regulates the expression of TFs responsible for glucose uptake and fatty acid oxidation, thus playing a critical role in maintaining insulin sensitivity. Thus, TFs such as PPAR$\gamma$ and uncoupling protein 1 (UCP-1) influence lipid accumulation, energy expenditure, and inflammatory responses in adipose tissue, all of which are integral to systemic insulin resistance [31].

Recent studies have focused on how some TFs, including anterior open (Drosophila ETS transcription factor) (AOP), FOXO, and pointed (Drosophila ETS transcription factor) (PNT), interact in hepatic and adipose tissues to change the metabolic rate and, as a result, longevity [10, 36]. In the skeletal muscle, factors such as fibroblast growth factor 19 (FGF19) stimulate glucose uptake and lipid metabolism through signalling pathways initiated by AMPK and sirtuin 1 (SIRT1), which control PGC-1$\alpha$ and fibronectin type III domain-containing protein 5 (FNDC-5) to modulate irisin secretion [10]. This transcriptional network illustrates how tissue-specific TFs cooperate to maintain insulin sensitivity and ameliorate metabolic disorders.

Insight into such interactions may provide a general understanding of possible therapeutic approaches that target TFs to improve insulin resistance and T2D. Such tissue-specific actions and systemic interactions of regulators may reveal unique ways to restore metabolic imbalance.

TFs are critical regulators of gene expression related to the inflammatory and immune responses. They are molecular switches that drive the expression of genes essential for various immune processes [13]. $\beta$-cell dysfunction, chronic inflammation, and insulin resistance are implicated in the dysregulation of these TFs.

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-$\kappa$B) is a common mediator of inflammation and $\beta$-cell destruction in autoimmune diseases and T2D [13]. Typically, this is mediated by the activation of NF-$\kappa$B in response to pro-inflammatory cytokines, such as TNF-$\alpha$, which upregulates genes that induce apoptosis, leading to the death of $\beta$-cells. Saturated fatty acids enhance the inflammatory response through NF-$\kappa$B activation and drive $\beta$-cell apoptosis [13]. Such an inflammatory milieu also impairs insulin signalling and further compromises $\beta$-cell function to promote the development [13, 17]. Therefore, NF-$\kappa$B plays a critical role and is an essential target for describing the relationship between inflammation and $\beta$-cell dysfunction [13].

The STAT family of TFs, particularly STAT4, have emerged as critical regulators in immune responses implicated in the pathogenesis of diabetes [8, 21]. Induction by cytokines, such as IL-12, triggers STAT4-dependent transactivation of IFN-$\gamma$, orchestrating TH1 immune responses [21]. Further induction of STAT4 activity due to diabetes promotes the production of proinflammatory cytokines, thus contributing to insulin resistance and chronic inflammation [21]. In contrast, deficiencies in STAT4 have been demonstrated to reduce such injurious effects, and thus have emphasised an essential role in the pathogenesis of T1D and T2D.

Interferon Regulatory Factors (IRFs) modulate the expression of chemokines in the context of chronic inflammation associated with diabetes and, by doing so, prolong the infiltration of immune cells into the sites of inflammation, creating a continuous inflammatory environment that contributes to insulin resistance and metabolic dysregulation [10, 37]. Abnormal IRF function disrupts the balance between pro- and anti-inflammatory mediators, characterising chronic inflammation in T1D and 2 diabetes [37, 38]. Therefore, the regulation of chemokines and inflammatory responses places IRFs in a critical role in the development of diabetes. IRF5 and AP-1 further exacerbate diabetic inflammation. The activation of IRF5 leads to M1 macrophage polarisation, which results in enhanced TNF-$\alpha$ and IL-6 production within adipose tissue [39]. Activation of AP-1 by IL-1$\beta$ in $\beta$-cells leads to decreased expression of PDX1 and MAFA, which results in faster dedifferentiation [40]. The use of antisense oligonucleotides to target IRF5 resulted in decreased islet inflammation in non-obese diabetic mice (NOD mice), which demonstrates therapeutic possibilities [39].

Chronic inflammation mediates a positive feedback loop by inducing several TFs that in turn promote $\beta$-cell destruction. Indeed, pro-inflammatory cytokines such as IL-1$\beta$ and TNF-$\alpha$ repress the expression of crucial $\beta$-cell identity genes, including insulin 2 (INS2) and SLC2A2, leading to $\beta$-cell dedifferentiation [10, 13]. Additionally, TGF-$\beta$ signalling initiates ST2 expression and directs the maturation of group 2 innate lymphoid cells (ILC2) which connects transcription factor-driven cytokine signaling with immune balance in adipose tissue and systemic metabolic control [41]. In this process, there is a significant downregulation or change in the mRNA levels of essential TFs, such as PDX1 and NKX6.1 [5, 11, 13]. Dedifferentiation of $\beta$-cells highly contributes to impaired glucose metabolism and inflammation; hence, NF-$\kappa$B is involved in this process.

Anti-inflammatory treatments decrease $\beta$-cell dysfunction, although they do not completely restore the expression of identity markers. Such effects to fully reverse $\beta$-cell dedifferentiation are limited, and suggest a role for targeted therapies in modulating TFs that may dampen the inflammatory response and protect $\beta$-cell function in diabetes.

$\beta$-Cell dysfunction and apoptosis are central events in the pathogenesis of diabetes, driven by the disturbed expression of crucial TFs that are sensitive to cellular stress [9]. FOXO1 and C/EBP homologous protein (CHOP) are significant regulators of $\beta$-cell stress response and apoptosis. FOXO1, induced by endoplasmic reticulum (ER) stress and exposure to fatty acids, drives the expression of pro-apoptotic genes, leading to $\beta$-cell apoptosis [9, 42]. Importantly, FOXO1 controls CHOP expression, thus regulating these two factors through a common apoptotic pathway. $\beta$-Cell death under stress was suggested to involve FOXO1, and its inhibition reduced apoptotic markers, thereby improving $\beta$-cell survival following its dual role in adaptation or dysfunction [9].

CHOP is an essential mediator of apoptosis after ER stress, and while necessary to maintain cellular homeostasis, it becomes deleterious after stress if it is highly activated [9]. This further complicates the understanding of $\beta$-cell dysfunction because of the interconnected nature of the transcriptional regulation of proapoptotic signals. FOXO1 and CHOP are essential for regulating $\beta$-cell apoptosis, and their dysregulation has been implicated in the pathogenesis of diabetes [9].

Another key player is represented by JNK and its corresponding JNK pathway, which is implicated in the $\beta$-cell ER stress response. Active JNK induces the expression of TFs such as activating transcription factor 3 (ATF3), which transactivates pro-apoptotic genes [43]. Although JNK activation is initially an adaptive reaction, under chronic hyperglycaemia and glucotoxicity conditions, its continuous activation leads to $\beta$-cell dysfunction and apoptosis [9, 43]. It is also associated with impaired insulin sensitivity in the liver, creating a vicious cycle caused by increased $\beta$-cell strain and accelerated $\beta$-cell exhaustion [43].

By its very nature, hyperglycaemia impairs the activity of key TFs, further promoting $\beta$-cell dysfunction. For example, high glucose levels induce hypoxia-inducible factor 1-alpha (HIF-1$\alpha$), which initiates inflammatory and pro-apoptotic pathways that adversely affect $\beta$-cell viability [37]. Hyperglycaemia disrupts the average balance of TFs that control insulin secretion, which reduces insulin biosynthesis and increases $\beta$-cell stress [37]. This differential expression underscores the multifaceted regulatory mechanisms by which TFs accomplish cellular homeostasis under normal conditions and contribute to metabolic stress and the consequent dysfunction [37, 38].

Other critical oxidative stress pathways, induced by activating certain TFs, also induce $\beta$-cell apoptosis [38]. Pro-inflammatory cytokines induce NF-$\kappa$B, which, in turn, upregulates the expression of inducible nitric oxide synthase (iNOS) and further generates peroxynitrite, a potent mediator of $\beta$-cell death [13, 37]. The persistent activation of the $\beta$-cell NLRP3 inflammasome increases endoplasmic reticulum stress and oxidative damage which triggers cell death and worsens $\beta$-cell loss in diabetes [44]. At the same time, oxidative stress triggers pro-apoptotic genes such as BH3-interacting domain death agonist (BID) and Cell death-inducing DFFA-like effector A (CIDE-A) and inhibits anti-apoptotic molecules such as B-cell lymphoma 2 (Bcl-2), thus tilting the balance toward apoptosis [37]. Additionally, JNK signalling also tips the balance by downregulating the promoter activity of Bcl-2 to amplify the apoptotic response to oxidative stress [42, 43].

Through interacting and regulatory networks, these TFs determine the balance between survival and apoptosis of $\beta$-cells [9]. Besides accelerating the deterioration in $\beta$ cell function, their dysfunction underlines the urgent need for focused therapeutic approaches to restore transcriptional homeostasis in islets from individuals with diabetes.

The connection between glucose metabolism (Fig. 3A), ER stress (Fig. 3B), reactive oxygen species (ROS) (Fig. 3C), NF-$\kappa$B (Fig. 3D), and cytokines (Fig. 3E) reveals how insulin production along with $\beta$-cell survival remains balanced across healthy conditions and disease states (Fig. 3).

Fig. 3.

Integrated pathways regulating insulin production and $\beta$-cell adaptation under metabolic stress and inflammation. This schematic illustrates a pancreatic $\beta$-cell, highlighting key pathways: (A) Glucose transporter type 2 (GLUT2) transporters help glucose enter pancreatic $\beta$-cells where glycolysis produces ATP that leads to the closure of ATP-sensitive potassium channel (KATP) channels and depolarizes the cell membrane to open voltage-gated calcium channel (VGCC)s. Insulin granule release occurs through calcium entry which also activates PDX1 and MAFA transcription factors to boost insulin gene expression. (B) Endoplasmic reticulum (ER) Stress Pathways: ER stress triggers C/EBP homologous protein (CHOP) activation which suppresses PDX1 protein levels to block insulin gene transcription. (C) Reactive oxygen species (ROS) Modulation: The regulation of FOXO1 function through ROS alters stress responses and impacts the lifespan of $\beta$-cells. (D) NF-$\kappa$B Pathway: NF-$\kappa$B becomes active because of ER stress and inflammatory processes resulting in both apoptotic cell death and impaired $\beta$-cell function. (E) Inflammatory Cytokines: TNF-$\alpha$ and interleukin (IL)-1$\beta$ (shown in the diagram) work together with stress signals to increase damage to $\beta$-cells. The interaction between glucose metabolism (A), ER stress (B), ROS (C), NF-$\kappa$B (D), and cytokines (E) shows how insulin production and $\beta$-cell survival balance under both normal and disease states (see Sections 2.1, 2.4). Created in BioRender.com. Simpson, A. (2025) https://BioRender.com/o94m886.

The development of diabetes involves contributions from non-beta islet cells through the action of transcription factors that include aristaless-related homeobox (ARX) in $\alpha$-cells and haematopoietically-expressed homeobox (Hhex) in $\delta$-cells [45]. The transcription factor ARX initiates and promotes glucagon production and increased levels of ARX aggravate hyperglucagonemia in T2D [45]. Hhex regulates somatostatin secretion, modulating insulin-glucose crosstalk [46]. Islet paracrine signaling becomes disrupted when TFs are deregulated, which reveals therapeutic targets across multiple cell types [45].

Specific TF pathways are implicated in the development of diabetic complications including retinopathy, nephropathy, and cardiovascular diseases [4]. Increased vascular endothelial growth factor (VEGF) levels due to HIF-1$\alpha$ activation under hyperglycemia initiates angiogenesis in diabetic retinopathy [47]. NF-$\kappa$B along, with TGF-$\beta$/SMAD3, initiates fibrosis in diabetic nephropathy through the activation of genes related to inflammation and fibrosis [18, 48]. The suppression of GATA6 by CEBPB in vascular smooth muscle cells regulates vascular calcification during atherosclerosis [22]. These pathways demonstrate how transcription factors can operate in distinct or unique ways, as well as share mechanisms in the development of diabetes and its subsequent complications.

TFs linked to diabetes control essential cellular functions by interacting with their target DNA-binding motifs, including positive regulatory domain III/positive regulatory domain I (PRDIII/PRDI) and AP-1 [50]. For instance, MafB activates the AP-1 motif, stimulating the cytokine promoter activity of genes such as interferon $\beta$1 (IFNB1), and represses over-activation at the positive regulatory domain III/positive regulatory domain I composite sequence (P31CS) motif, thereby hindering the cell from hyperactivity. Paired box 4 (PAX4) regulates the immune response, cell cycle, and DNA damage response pathways. It is one of the most important TFs that enhances neogenesis and survival of $\beta$-cells under stress [54]. Post-translational modifications further modulate TF activity. The PDX1 promoter experiences DNA hypermethylation due to hyperglycaemia which leads to its expression silencing and increases the rate of $\beta$-cell dedifferentiation [55]. Chromatin remodelling complexes further modulate the activity of TFs by changing the chromatin conformation in a way that can be permissive or nonpermissive to DNA accessibility and subsequent gene transcription [49]. The dynamic nature of gene expression regulated by these complexes involves acetylation and deacetylation of histones in response to metabolic signals [56]. In addition, TFs such as FOXO1 and PDX1 are highly regulated through feedback mechanisms in the balance of glucose metabolism, insulin signalling, and inflammatory responses via Akt/PI3K and mitogen-activated protein kinase (MAPK), which are important for $\beta$-cell function and metabolic homeostasis [14, 34].

Generally, post-translational modifications are essential for fine-tuning the activity of the TFs involved in diabetes. Phosphorylation is likely the most important process in post-translational mechanisms. Phosphorylation is expected the most important step in these processes. FOXO1, for instance, undergoes insulin-induced phosphorylation at sites such as Thr-24, Ser-256, and Ser-319, which prevents its translocation into the nucleus and causes its retention in the cytoplasm, thereby hindering its transcriptional activity [14]. Furthermore, the phosphorylation of Ser-256 may be subjected to additional phosphorylation events that allow interaction with nuclear export proteins. Similarly, phosphorylation affects TFs such as SREBP1c, where signalling pathways regulate its expression via factors such as specificity protein 1 (Sp1) and liver X receptor (LXR), modulating the transcription of target genes [14].

Ubiquitination affects the stability of TFs. For example, the E3 ligase F-box/WD repeat-containing protein 7 (FBW7) targets enhancer of zeste homolog 2 (EZH2) for proteasomal degradation [14]. Lower levels of FBW7 in T1D favour the stability of EZH2 and enhance $\beta$-cell inflammation and apoptosis [14]. In contrast, degradation of EZH2 by FBW7 upregulates the transcription factor zinc finger and BTB domain-containing protein 16 (ZBTB16), favouring insulin signalling and mitochondrial function, thus underlining the FBW7-EZH2-ZBTB16 axis as a therapeutic target [14].

Under ER stress FOXO1 becomes Sumoylated which maintains its nuclear localisation and increases the activity of pro-apoptotic genes such as CHOP [9, 57, 58]. The study reveals that sumoylation of NF-$\kappa$B homologs including Dorsal reduces Toll/NF-$\kappa$B signaling which shows how sumo modifications regulate inflammatory transcription factor function [57]. Metabolic stressors activate modifications which lead to transcriptional dysregulation [58]. For example, the diabetes-associated variant paired box 4 Arg129Trp variant (PAX4R129W) abrogates this protective function by reducing adaptive gene expression, such as cyclin D3, and simultaneously upregulating pro-apoptotic factors, including cyclin-dependent kinase inhibitor 2A (CDKN2A), thus negatively affecting $\beta$-cell proliferation and survival [54, 59]. Upregulation of CDKN2A (p16INK4a), promotes cell-cycle arrest. Increased expression of CDKN2A mRNA is a transcriptomic marker of clinically aggressive meningiomas, which is also consistent with a more general role for this gene in regulation of disease-associated proliferation [60].

Acetylation and deacetylation are dynamic epigenetic modifications that regulate the extent of gene expression. Histone acetyltransferases (HATs) catalyse the addition of an acetyl group to histones, maintaining an open configuration of chromatin with active transcription [61]. On the contrary, histone deacetylases remove the acetyl groups from histones, enabling chromatin’s condensation and inhibiting transcription [56, 61]. The process of DNA repair is regulated by histone deacetylase 1 (HDAC1) and HDAC2 histone deacetylases, either directly altering the key histone residues histone H3 lysine 56 (H3K56) and H4K16, which affect the choice of repair pathway [51]. The other family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases consists of sirtuins, which regulate stress responses and metabolic processes, and thus participate in maintaining cellular homeostasis under conditions of metabolic stress.

Sumoylation is the post-translational attachment of small ubiquitin-like modifier proteins that links the stability, localisation, and activity of TFs to oxidative or metabolic stress [43, 53]. This modification supports cellular adaptation because it mechanistically influences the expression of stress-related genes that are essential for maintaining homeostasis and evading apoptosis [42, 43].

miRNAs are important post-transcriptional regulators of gene expression through the specificity of their binding to mRNAs, leading to either the prevention of translation or the degradation of these mRNAs [62]. For instance, miR-709 was previously identified to directly target the TFs CCAAT enhancer-binding protein $\alpha$ (CEBPA) and Myelocytomatosis oncogene (MYC), which play a role in glucose metabolism and $\beta$-cell function, and its dysregulation has been associated with impaired insulin secretion and $\beta$-cell failure, thus playing a role in the development of diabetes [63, 64]. These transcriptional regulatory networks play important roles in maintaining cellular functions and orchestrating the response to metabolic stress associated with diabetes.

Epigenetic modifications determine the activity of transcription factors that control gene expression and influence the development of diabetes. Transcription factor expression shows a connection with DNA methylation which functions as a crucial epigenetic mechanism through changes in the methylation status of cytosine-phosphate-guanine dinucleotide (CpG) sites [65, 66]. Environmental exposure may induce methylation changes in genes that control inflammation, which is a risk factor for the development of diabetes. For example, DNA methylation may target TFs, such as bromodomain-containing protein 4 (BRD4) and basic leucine zipper ATF-like transcription factor 3 (BATF3), which repress the expression of their respective genes or be deposited on their target genes, thus preventing correct target regulation by these factors. The methylation pattern changes impact both immune responses during cytomegalovirus infection and diabetes susceptibility [65]. The mentioned case stands as a single instance demonstrating how methylation changes control diabetes-related biological processes.

Post-transcriptional control by miRNAs functions as a vital mechanism for gene expression regulation in diabetes beyond DNA methylation. miRNAs are small molecules of non-coding RNA which attach to specific mRNA targets which results in mRNA degradation or translational blockage. The microRNA miR-709 targets transcription factors CEBPA and MYC directly which affect glucose metabolism and $\beta$-cell function. The malfunction of miR-709 leads to defective insulin release and $\beta$-cell malfunction which demonstrates its importance in the progression of diabetes [63]. miRNAs establish connections with epigenetic regulators including DNA methyltransferases and histone deacetylases to form a multifaceted regulatory system that affects $\beta$-cell operation and insulin response. Thus, miRNAs represent an additional layer of gene expression control that complements traditional epigenetic mechanisms in diabetes.

Non-coding RNAs include long non-coding RNAs (lncRNAs) and miRNAs, which are major regulators of epigenetic modifications of transcription factor genes. lncRNAs can act as circRNAs (ccRNAs), thus regulating miRNA availability and the number of TFs [67]. lncRNA myocardial infarction-associated transcript (MIAT) affects transcription factor expression indirectly by changing intracellular signalling, which includes TGF-$\beta$. The interplay between these non-coding RNAs and transcription factors influences the expression of diabetes-associated genes [67].

Histone modifications including acetylation and methylation are essential for chromatin accessibility and transcriptional activity. High levels of acetylated histone three (H3) within myoblasts with reduced vacuolar protein sorting associated protein 39 (VPS39) indicate disturbances in the differentiation processes associated with diabetes [65]. In a somewhat related scenario, high glucose levels cause changes in the degree of histone acetylation, for example, histone 3 lysine 9 and 14 (H3K9/K14), and reduce repressive trimethylation marks on H3K9, thus allowing for the perpetual activation of inflammatory genes, such as IL-6 and monocyte chemoattractant protein 1 (MCP-1) [51]. Increased lipid levels, including oxidised low-density lipoprotein (LDL), trigger active epigenetic reprogramming and maintain both proinflammatory responses and metabolic disorders. Hence, environmental stressors such as high glucose and lipid levels would strongly influence epigenetics, particularly in endothelial cells and monocytes, resulting in long-lasting changes in gene expression observed in metabolic and cardiovascular disorders [65]. The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) maintains NF-$\kappa$B transcripts in macrophages, which leads to increased islet inflammation during T1D [67, 68]. T2D involves impaired glucose detection due to decreased H3K27ac histone marks at MAFA enhancers and increased lipogenic gene expression due to hyperacetylation at SREBP1c promoters [68]. Environmental signals interact with transcription factor activity through epigenetic layers to determine the characteristics of diabetic phenotypes [65].

Epigenetic therapies targeting DNA methyltransferases (DNMTs) and HDACs are promising approaches for restoring transcription factor regulation in diabetes [65]. Dietary extremes of lipid and carbohydrate consumption, as defined by the IDECG Working Group, have been shown to modulate DNA methylation patterns and thereby alter transcription factor accessibility and downstream gene expression [69]. Simultaneously, HDAC inhibitors improve histone acetylation, thereby increasing chromatin openness and transcriptional activity [65]. Such epigenetic therapies could offer a potential approach for correcting dysregulated gene expression and slowing diabetes progression Table 3 (Ref. [31, 50, 56, 70, 71]) summarises epigenetic modifications influencing TFs and their clinical implications in diabetes.

Transcriptional activators based on the clustered regularly interspaced short palindromic repeats/deactivated Cas9 system (CRISPR/dCas9) system allow targeted overexpression of PDX1 in $\beta$-cells while avoiding DNA sequence alterations [80]. Targeting the PDX1 promoter with deactivated Cas9 fused to the VP64 transcriptional activation domain (dCas9-VP64) systems successfully restored insulin secretion in human islets. Lipid nanoparticles (LNPs) which contain glucagon-like peptide 1 (GLP-1) receptor ligands specifically target pancreatic islets to transport siRNA against NF-$\kappa$B and decrease inflammation while avoiding systemic immune suppression [81, 82].