Epigenetic regulation in a high-sugar environment (Review)

Introduction

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both (1). Clinically, diabetes mellitus is primarily categorized into Type 1 diabetes (T1DM, accounting for 5-10%) and Type 2 diabetes (T2DM, accounting for 90-95%). T1DM is chiefly caused by absolute insulin deficiency resulting from autoimmune-mediated destruction of pancreatic islet β-cells; whereas T2DM is characterized by insulin resistance accompanied by relative insufficiency in insulin secretion. Diabetes has become an epidemic disease (2), with China's prevalence projected to rise to 592 million by 2035 (3). Chronic hyperglycemia also disrupts insulin secretion and/or function and is associated with long-term damage and dysfunction in various tissues and organs (eyes, kidneys, nerves, heart and blood vessels) as well as cancer (4). The management of diabetes and its complications remains a significant challenge, particularly diabetic kidney disease (DKD). Existing biomarkers as therapeutic targets only partially mitigate DKD progression and provide rough predictions of disease advancement. When diabetes coexists with cardiovascular disease (CVD), mortality nearly doubles (5). Even after restoring normal blood glucose and metabolic balance, the effects of hyperglycemia on diabetes and its complications do not immediately reverse; a phenomenon termed 'metabolic memory' (6-8). Metabolic memory primarily manifests as epigenetic alterations in target cells under diabetic conditions (9). Since epigenetic modifications are often reversible, this offers therapeutic opportunities to improve cellular dysfunction and mitigate or 'erase' metabolic memory (10).

Epigenetics refers to the study of heritable phenotypic changes that do not involve alterations in DNA sequences (11-13). Research in epigenetics has shown a rapid growth trend (14). DNA methylation, histone modifications and non-coding RNA regulation are three major research directions in epigenetics (15). Epigenetic research not only provides new perspectives for understanding gene expression regulation but also offers novel approaches for disease prevention and treatment (16). For instance, by modulating epigenetic modifications, novel therapeutic strategies can be developed to combat environmentally induced diseases such as CVD, diabetes and cancer. Furthermore, epigenetic markers serve as diagnostic biomarkers for diseases, underpinning personalized treatment and precision medicine (17).

Emerging epigenetic tools can be used for the prevention, diagnosis and treatment of diabetes and its complications (18). Therefore, investigating epigenetic variations under high-sugar environments and their regulatory roles in diabetes progression holds significant potential for clinical applications in diabetes diagnosis and therapy (19). The present review primarily introduced the epigenetic regulatory mechanisms of high-sugar microenvironments across different cell types and disease models, offering novel insights for treating diabetes and its complications through epigenetic modulation. The present review uniquely integrates findings across pancreatic, hepatic, vascular and renal systems to provide a holistic view of the epigenetic landscape reshaped by hyperglycemia.

Epigenetic regulatory mechanisms of high glucose on cells

High glucose and cellular DNA methylation

DNA methylation is one of the most common epigenetic modifications (20), primarily occurring on cytosine residues. Specifically, methylation typically occurs within CpG dinucleotides (21). The addition of a methyl group leads to gene expression suppression, as methylated DNA often binds to transcription factors, preventing RNA polymerase binding and thereby inhibiting gene transcription (22). DNA methylation is frequently associated with gene silencing (23). For instance, in tumor cells, tumor suppressor genes may lose expression due to hypermethylation (24,25). Concurrently, DNA methylation influences genomic stability, participating in processes such as genomic imprinting and X chromosome inactivation (26). A high-sugar environment, particularly prolonged exposure to elevated glucose levels, induces significant alterations in DNA methylation within pancreatic β-cells (27), potentially disrupting insulin secretion and metabolic function. DNA methylation is primarily catalyzed by DNA methyltransferases (DNMTs) (28,29), involving the transfer of methyl groups onto cytosine residues in DNA. Methylation levels and patterns are influenced by multiple factors, including dietary habits, environmental factors and genetic background (30). A high-sugar diet affects DNA methylation levels by influencing one-carbon metabolism pathways, increasing the availability of methyl donors such as S-adenosylmethionine (31). However, excessive methyl donors may also lead to methylation suppression, highlighting the complexity of high-sugar environments (32). Research indicates that glucose excess induces increased methylation density in specific genes, thereby suppressing their expression (27). For example, Vigorelli et al (33) found that methylation levels in the promoter region of the C-X-C motif chemokine receptor 4 (CXCR4) gene in human CD34+ stem cells markedly increased under high-sugar conditions, affecting cellular proliferation and migration capabilities. Furthermore, high glucose also affects the methylation status of genes associated with insulin signaling pathways, lipid metabolism and inflammatory responses, potentially contributing to the development of diseases such as metabolic syndrome, obesity and T2DM (34). Table I describes some genes undergoing DNA methylation changes influenced by high glucose (34-44).

Table I Genes affected by high sugar exposure in terms of DNA methylation.

Table I

Genes affected by high sugar exposure in terms of DNA methylation.

Authors, year	Cell type	Species	Gene	Effect	Consequence	(Refs.)
Gill et al, 1994	Hepatocytes	Female mice	Sult1e1	DNA methylation	Impaired angiogenesis	(35)
Jain et al, 2011	Vascular endothelial cells	Homo sapiens	IL-8	DNA methylation	Endothelial dysfunction	(36)
Hamad et al, 2021	INS-1	Rat	Hmox1	DNA methylation	Oxidative stress diabetic	(37)
Chen et al, 2020	Human retinal venules	Human and Porcine	Endothelin-1	DNA methylation	Diabetic retinopathy	(38)
Jurado-Aguilar et al, 2024	Hepatocytes	Wild-type and Gdf15-/- mice	SMAD3	DNA methylation	Vascular remodeling	(39)
Tewari et al, 2012	Retinal endothelial cells	Streptozotocindiabetic rats	Polg1	DNA methylation	Transcriptional repression	(40)
Park et al, 2008	Pancreatic beta cells	Rats	PDX1	DNA methylation	Insulin resistance	(41)
Ding et al, 2012	Pancreatic islet cells	GDM(F1-GDM) mice	Igf2/H19	DNA methylation	Impaired glucose tolerance	(42)
Zhang et al, 2019	HRECs	Diabetic mice	NF-kB	DNA methylation	Inflammation	(43)
Gunes et al, 2023	LX-2	Homo sapiens	IL-6	DNA methylation	Fibrosis	(44)

[i] Sult1e1, estrogen sulfotransferase 1E1; IL, interleukin; Hmox1, heme oxygenase 1; polg1, polymerase γ1; PDX1, pancreatic and duodenal homeobox 1; Igf2, insulin-like growth factor 2; H19, imprinted maternally expressed transcript; NF-kB, nuclear factor-κB; INS-1, insulinoma cell line-1; HRECs, human retinal endothelial cells; LX-2, human hepatic stellate cell line-LX-2.

Histone modifications

Histones are proteins around which DNA is wound, forming the fundamental units of chromatin (45,46). Modifications of histones include methylation, acetylation, phosphorylation, ubiquitylation, ADP-ribosylation, SUMOylation and other novel modifications, which can directly influence chromatin structure (47). Different histone modification states are closely associated with gene activity levels (48). For example, acetylation is typically linked to transcriptional activation (49), while methylation can lead to transcriptional repression (50).

Histone modifications in high-sugar environments

In high-sugar environments, the most common histone modification type includes histone acetylation. Histone acetylation occurs when acetyltransferases (such as CBP and p300) add acetyl groups to histone lysine residues. This modification leads to chromatin relaxation, making DNA more accessible to transcription factors and other regulatory proteins, thereby promoting gene transcription (51). Biernacka et al (52) discovered that high-glucose-treated LNCaP cells (a human prostate cancer cell line) exhibited markedly increased histone H3 acetylation associated with the insulin-like growth factor binding protein 2 gene, leading to chemotherapy resistance in prostate cancer (PCa). High glucose also induces histone H3 methylation (53). Histone methylation refers to the addition of methyl groups to lysine or arginine residues on histone proteins. Depending on methylation levels, histone methylation can either promote or suppress gene transcription. For example, tri-methylation of lysine 4 on histone H3 catalyzed by histone methyltransferases (H3K4me3) is typically associated with gene activation, whereas H3K27me3 is often linked to gene silencing (54,55). Ishikawa et al (56) discovered that in type 2 diabetes mellitus (T2DM), increased expression and decreased methylation of the cyclin-dependent kinase inhibitor 1A and phosphodiesterase 7B in T2DM exhibit increased expression and reduced methylation. This combination impairs glucose-stimulated insulin release by inhibiting β-cell proliferation, promoting apoptosis and disrupting cAMP signaling pathways (56). In a study of Drosophila oocytes, Sun et al (57) found that under high-sugar conditions, histone H3 methylation levels (such as, H3K9 and H3K27) increase, suppressing cyclin D1 gene expression and disrupting cell cycle progression, thereby impairing early embryonic development.

High sugar and lactylation

Lactylation is a newly discovered post-translational modification of proteins. It uses lactate, the end product of glycolysis, as a substrate to covalently attach a lactyl group to lysine residues on both histone and non-histone proteins (58). In high-glucose microenvironments, cellular metabolic pathways undergo significant alterations that directly influence lactylation levels, targets and functions, thereby driving disease progression in conditions including cancer and diabetic complications (59).

The high-glucose microenvironment drives cellular metabolic reprogramming via the Warburg Effect, causing cells to preferentially metabolize glucose through efficient glycolysis even under oxygen-sufficient conditions. This process leads to a substantial increase in intracellular lactate production. Research confirms that high-glucose conditions specifically upregulate L-lactic acid levels, while D-lactic acid remains unaffected. This indicates that hyperglycemia primarily rewrites the cellular modification profile through the L-lactic acid pathway (60).

In a high-sugar environment, lactylated histone modifications do not simply increase overall but exhibit site-specific enrichment and functional reprogramming. The hyperglycemic microenvironment induces elevated levels at specific histone lactylation sites, with H3K18la and H3K9la being the most characteristic sites (61). For instance, in diabetic retinopathy models, hyperglycemia/hypoxia triggers explosive increases in H3K9la and H3K18la in retinal endothelial cells, thereby activating transcription programs of pro-angiogenic genes. Evidence also shows that, Alanyl-tRNA synthetase 1 acts as a lactyltransferase to modulate H3K18, thereby regulating elongase-5 transcription and mediating ferroptosis in individuals with DKD (62).

Abnormally expressed histone modifying enzymes in high-glucose environments

Research indicates that elevated glucose levels induce abnormal expression of certain histone modification enzymes (63). Altered activity of these enzymes directly modifies histone modification states, thereby affecting gene transcriptional activity (64). For example, Sánchez-Ceinos et al (65) found that the histone lysine N-methyltransferase (enhancer of Zeste 2 polycomb repressive complex 2 subunit) increases under high glucose conditions in both human aortic endothelial cells (HAECs) exposed to high glucose in vitro and those isolated from individuals with diabetes (D-HAECs). This leads to elevated H3K27me3 levels and the oxidative stress driven by H3K27me3 enhances nuclear factor κB p65 (NF-κB p65) activity, ultimately causing endothelial dysfunction (65). Furthermore, Miao et al (66) found that high-glucose-treated monocytes exhibited increased transcriptional activity of histone acetyltransferases CBP (CREB-binding protein) and p/CAF (p300/CBP-associated factor), leading to elevated levels of HH3 (histone H3) acetylation at TNF-α and COX-2 promoters in monocytes in human blood monocytes from type 1 and type 2 diabetic. This alteration promotes the expression of metabolism- and inflammation-related genes such as NF-κB (66).

High-glucose-induced histone modifications and gene expression regulation

Changes in histone modifications induced by high-sugar environments directly influence gene expression. For example, Sun et al (67) found P/CAF acetylated lysine residues 328 and lysine 450, in liver cells from mice treated with high glucose, leading to proteasomal degradation and increased blood glucose and hepatic glucose output. Yamazaki et al (68) also found that H3K9 acetylation (H3K9ac) is elevated in the promoter region of the high glycated hemoglobin group in blood lymphocytes and monocytes from type 1 diabetes mellitus patients, according to the report on histone modification status. H3K9ac also influences NF-κB expression, with studies indicating that increased H3K9ac correlates with inflammation-induced progression of DKD (69). A high-sugar environment not only affects individual gene expression but also, as research shows, a high-sugar diet can alter the epigenetic state of pregnant women, leading to genomic changes in their offspring (70). For example, leptin gene (LEP) is a gene regulating energy balance. Allard et al (71) demonstrated through a Mendelian randomization study that maternal hyperglycemia reduces LEP DNA methylation levels in offspring and correlates with elevated umbilical cord blood leptin levels. This suggests that in utero-induced epigenetic regulation may contribute to increased obesity rates later in life (71-73). Table II describes the histone modifications induced by high sugar in certain genes (65,74-78).

Table II High-sugar-induced histone modifications in selected genes.

Table II

High-sugar-induced histone modifications in selected genes.

Authors, year	Cell type	Species	Target gene	Histone modification	Regulation	Consequence	(Refs.)
Sánchez-Ceinos et al, 2024	D-HAEC	Human	EZH2	Histone methylation	↑	Endothelial oxidative stress	(65)
Malmgren et al, 2013	Pancreatic β-cell	Human	UTX and JMJD3	Histone demethylation	↓	Endothelial oxidative stress	(74)
Liao et al, 2022	HepG2, L02 and A673 cells	Mice	GCN5	Histone acetylation	↑	Glucose uptake inhibition	(75)
Lee et al, 2018	293 cells	Sprague-Dawley rats	HDACs	Histone deacetylation	↑	Reduced transcriptional activity	(76)
Horitani et al, 2021	EPCs	Mice	H3K27me3	Histone demethylation	↑	Atherosclerosis	(77)
Qiu et al, 2020	Pancreatic β cells	Mice	IL-17A	Histone acetylation	↑	Inflammation	(78)

[i] ↑, upregulation; ↓, downregulation; D-HAEC, diabetic human aortic endothelial cells; HepG2, L02 and A673 cells, human hepatocellular carcinoma G2, human normal liver L02 cells and A673 rhabdomyosarcoma cell line; 293 cells, 293 cells; EPCs, endothelial progenitor cells; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; UTX and JMJD3, KDM6A and KDM6B; GCN5, general control non-derepressible 5; HDAC, histone deacetylase; H3K27me3, Tri-methylation of lysine 27 on histone H3; IL-17A, interleukin-17A.

Effects of high-glucose environment on non-coding RNA expression and consequences

Non-coding RNAs refer to RNA molecules that do not encode proteins, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) (79). They play crucial roles in regulating gene expression. Non-coding RNAs possess several important functions, including: i) Transcription regulation: Non-coding RNAs influence gene transcription levels by modulating the activity of transcription factors (80); ii) Splicing functions: Certain lncRNAs can influence mRNA splicing processes, thereby altering the final protein product type (81); iii) Stabilizing mRNA molecules: Non-coding RNAs can bind to mRNA, affecting its stability and degradation rate; iv) Regulating translation: By binding to translation-related factors, ncRNAs can modulate mRNA translation efficiency.

Research indicates that under high-glucose/diabetes conditions, the expression of certain non-coding RNAs undergoes significant alterations (82). These changes may be mediated through the following mechanisms: i) Modulating transcription factor activity: High glucose levels induce alterations in the activity of specific transcription factors, which in turn regulate the expression of particular lncRNAs. For instance, Zhang et al (83) observed that in genetically diabetic C57BKS mouse cells, signal transducer and activator of transcription 1 phosphorylation markedly upregulates metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) expression and downregulates miR-205 expression through the JAK-STAT signaling pathway, disrupting epithelial-mesenchymal transition (EMT) and impairing wound healing in patients with diabetes. ii) Epigenetic modifications: A high-sugar environment may also indirectly regulate non-coding RNA expression by affecting DNA methylation and histone modifications. For example, in a study on gestational diabetes mellitus (GDM), Li et al (84) found that the NADPH oxidase 5 gene exhibited higher methylation levels in the peripheral blood of GDM pregnant women, indirectly leading to the lncRNA RPL13P5 forming a co-expression network with the TSC complex subunit 2 gene through the PI3K/AKT signaling pathway, thereby inhibiting pancreatic islet β-cell growth and reducing insulin secretion under both hypoglycemic and hyperglycemic conditions.

In high-glucose environments, specific non-coding RNAs have been identified as closely associated with insulin signaling and glucose/lipid metabolism. For instance, maternally expressed gene 3 (Meg3), an lncRNA located on human chromosome 14q32, is upregulated under hyperglycemic conditions. It induces ferroptosis by activating the p53 pathway (85). Abnormal Meg3 expression may be closely linked to diabetes development. In diabetic mice, the lncRNA H19 exhibits reduced expression levels in hepatocytes. It enhances hepatic gluconeogenesis and glucose output by regulating the MAPK, PI3K/Akt and mTOR signaling pathways (86). Wu et al (87) further discovered that in high-glucose-induced mouse hepatocytes, downregulated miR-206 impairs lipogenesis and promotes insulin signaling by regulating the PTPN1-INSR/IRS and PTPN1-PP2A-SP1-Srebp1c pathways. Table III describes the effects of high glucose on the expression of selected ncRNAs (88-94).

Table III Effects of high glucose on non-coding RNA expression.

Table III

Effects of high glucose on non-coding RNA expression.

Authors, year	Cell or disease	Species	Non coding RNA (lncRNA or microRNA)	Regulation (↑or↓)	Consequence	(Refs.)
Pradas-Juni et al, 2020	DIO	Mice	lincIRS2	↓	Insulin resistance	(88)
Cui et al, 2018	Hepatocytes	Mice	GM10768	↑	Gluconeogenesis	(89)
Li et al, 2024	Keratinocytes	Human	miR181A2HG	↑	Anti-angiogenesis	(90)
Zhao et al, 2020	Microglia	SD female rats	lncRNA-Gm4419	↓	Apoptosis	(91)
Liu et al, 2021	HUVECs	Human	PVT1	↑	Oxidative stress	(92)
He et al, 2020	Adipose-derived stem cell	Human	MALAT1	↑	Podocyte injury	(93)
Heydari et al, 2023	Type 2 diabetes	Human	TUG1	↓	Regulation of mitochondrial function	(94)

[i] ↑, upregulation; ↓, downregulation; DIO, obesity; HUVECs, human umbilical vein endothelial cells; lincIRS2, a long intergenic non-coding RNA that regulates insulin receptor substrate 2; PVT1, plasmacytoma variant translocation 1; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; TUG1, taurine up-regulated gene 1.

Differences in the epigenetic regulation of high glucose on different cell types

A high-sugar environment influences gene expression in different cell types through multiple epigenetic mechanisms, specifically manifested in alterations such as DNA methylation, histone modifications and non-coding RNAs. These changes may lead to abnormal cellular functions, thereby affecting organismal health.

Epigenetic regulation of pancreatic islet cells by high glucose

In pancreatic islet cells from patients with T2DM, epigenetic variations cause β-cell dysfunction, manifesting as reduced insulin secretion and insulin resistance (95). Research indicates the existence of functionally distinct β-cell subtypes within islets, which may possess different epigenetic backgrounds and regulatory specificities, playing a crucial role in insulin secretion and blood glucose regulation (96).

In pancreatic islet cells, high glucose regulates epigenetic variation through the following mechanisms: i) Enhancing transcriptional activity: For example, Bevacqua et al (97) discovered in an adult pancreatic islet study that exposure to high glucose concentrations activates the histone methyltransferase SET domain containing 7, histone lysine methyltransferase in pancreatic β cells. This enzyme catalyzes the H3K4me1 in the PDX-1 gene promoter region. This epigenetic modification leads to chromatin relaxation, facilitating PDX-1 binding to the promoter and enhancing its transcriptional activity. This binding further induced methylation modifications on the PDX-1 protein itself (such as K91 site methylation), forming a positive feedback loop that impaired glucose-stimulated insulin secretion (GSIS) (97). ii) Regulation of signaling pathways: Hyperglycemia can influence the epigenetic characteristics of pancreatic islet cells through multiple signaling pathways. For example, hyperglycemia regulates mitochondrial autophagy via the PI3K/Akt/mTOR pathway, thereby impairing pancreatic β-cell function. Under fluctuating hyperglycemic conditions, elevated DNMT activity causes hypomethylation in the miR-99 gene promoter region (CpG island demethylation), releasing transcriptional repression of miR-99. Elevated miR-99 suppresses the PI3K/Akt/mTOR pathway in pancreatic β-cells, leading to increased mitochondrial autophagy and consequently inhibiting β-cell proliferation and insulin secretion (98).

Epigenetic regulation of hepatocytes by high glucose

A high-glucose environment may regulate hepatocyte function by influencing epigenetic mechanisms. For example, elevated glucose concentrations promote O-GlcNAc glycosylation modification at serine and threonine residues of the transcriptional regulatory protein tet-methylcytosine dioxygenase 1 (TET1), thereby activating TET1 protein function. TET1 catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, initiating DNA demethylation processes that promote inflammatory responses and oxidative stress in hepatocytes (99,100). High glucose also affects hepatocyte function by inducing epigenetic variations that alter cellular signaling pathways. Wang et al (101) discovered that SIRT1 (NAD-dependent histone deacetylase) is downregulated in HG-treated hepatocytes. This deficiency leads to suppressed mTORC2 activity and Akt dephosphorylation, resulting in upregulation of gluconeogenic genes (glucose-6-phosphatase, catalytic subunit, phosphoenolpyruvate carboxykinase 1) and insulin resistance in mice (102).

High concentrations of glucose can activate multiple transcription factors in liver cells, which play crucial roles in glucose and lipid metabolism. For example, Yun et al (103) found that elevated glucose levels activate NF-κB in human monocytic (THP-1) cells, a key inflammatory transcription factor. Activation of NF-κB induces the expression of miR-146 and miR-155. miR-146 contributes to insulin resistance by regulating gene expression in the insulin signaling pathway, while miR-155 promotes fatty liver development by modulating suppressor of cytokine signaling 1 (SOCS1) expression (103). Multiple transcription factors also interact with each other under high glucose conditions. The glucose-responsive transcription factor carbohydrate response element binding protein (ChREBP) is a key regulator of hepatic lipogenesis. Together with upstream stimulating factor 1 (USF1), it activates the transcription of lipogenic genes, thereby regulating lipid synthesis in the liver (102). When glucose levels rise, ChREBP is activated by acetylation at the K672 site by p300 (an acetyltransferase). It then synergizes with USF1 to influence the conversion of fatty acids into triglycerides for storage via the PI3K/AKT pathway, thereby enhancing lipid synthesis in hepatocytes (103). This interaction holds significant importance in both glucose and lipid metabolism. Liver X receptor alpha (LXRα) in THP-1 is another key transcription factor that positively regulates GLUT4 expression. Under high-glucose conditions, LXRα expression is upregulated. It interacts with JMJD1C (an H3K9 histone demethylase), leading to H3K9 demethylation and subsequent promotion of GLUT4 expression, thereby enhancing hepatic lipogenesis (103).

High glucose-induced DNA methylation in hepatocytes is another common epigenetic phenomenon. Studies indicate that high glucose affects the methylation status of certain genes in hepatocytes, potentially leading to disorders in glucose and lipid metabolism. For example, Krause et al (104) demonstrated that in T2DM, sterol regulatory element-binding protein 1c (SREBP-1c, a key transcription factor that binds to the SRE sterol regulatory element within the promoters of lipogenic genes to enhance their transcription) exhibits hypomethylation at CpG sites, impairing its transcription. This enhances IRS-2 expression and induces excessive lipidsynthesis via the PI3K/Akt pathway, closely associated with hepatic steatosis (104,105).

Epigenetic regulation of muscle and adipose cells by high glucose

Epigenetic alterations induced by high glucose concentrations in human cells markedly affect metabolic functions in muscle and fat cells. These epigenetic changes not only influence gene expression but are also closely associated with the development of T2DM and obesity.

In a high-glucose environment, the metabolic function of muscle cells is markedly impaired. Research indicates that high glucose levels induce insulin resistance, thereby reducing glucose uptake in muscle and adipose tissue while promoting hepatic glucose release. Friedrichsen et al discovered that in the muscles of patients with T2DM, genes associated with mitochondrial function, such as ubiquinone oxidoreductase subunit B6 and cytochrome c oxidase subunit 7A1 exhibit elevated DNA methylation levels, impairing NADH oxidation. This subsequently blocks the PI3K/Akt pathway, leading to insulin resistance in muscle cells (106). The acetylation or deacetylation status of histones in muscle cells is also affected by high glucose. Research indicates that increased histone acetylation correlates with enhanced muscle cell metabolic activity, whereas high glucose environments activate deacetylases, thereby suppressing muscle cell metabolism and reducing glucose utilization efficiency (107). High glucose also modulates muscle cell signaling pathways, inducing epigenetic alterations. For instance, activation of the mTOR pathway typically drives cell growth by promoting anabolic processes and inhibiting catabolism. Saha et al (108) discovered that under high glucose conditions, mTORC1 phosphorylates the T505 site of the JMJD1C protein and inhibits LC3-II activity. LC3-II is a hallmark protein for autophagosome formation; its suppressed activity reduces cellular autophagy levels, leading to abnormal proliferation of muscle cells. Since JMJD1C is established as a histone demethylase, its phosphorylation specifically enhances H3K9me2 demethylation in muscle cells, particularly in promoter regions of muscle differentiation-related genes (such as MyoD). This epigenetic modification promotes the upregulation of myogenic transcription factors such as MyoD, ultimately accelerating muscle cell differentiation and enhancing glucose metabolism capacity (108).

Adipocytes play a crucial role in energy storage and metabolic regulation. Under high glucose concentrations, the epigenetic regulation of adipocytes also exhibits significant alterations. In a high-glucose environment, adipocytes promote lipogenesis by modifying epigenetic modifications. For instance, Stegemann and Buchner (109) discovered that methylation occurs in the promoter region of the peroxisome proliferator-activated receptor gamma (PPARγ) gene under high-sugar conditions, thereby promoting lipogenesis (109-112). High glucose also disrupts insulin signaling pathways in adipocytes, a disruption often associated with epigenetic alterations. For example, miR-150 regulates lipogenesis in bovine preadipocytes via the mTOR signaling pathway (111). A high-glucose environment can also induce inflammatory responses within adipocytes through epigenetic mechanisms. For instance, Zhao et al (91) found that Gm4419 (a long non-coding RNA) regulates mesangial cell inflammatory factor expression via the NF-κB signaling pathway under high-glucose conditions, thereby promoting chronic low-grade inflammation and damaging adipose tissue, a process closely linked to obesity and metabolic syndrome (113,114).

Epigenetic regulation of different diseases by high glucose

Hyperglycemia, a clinically prevalent metabolic abnormality, can trigger multiple diseases including diabetes, DKD, diabetic CVD and diabetic retinopathy. Under identical high-sugar conditions, the cellular behavioral changes induced in different diseases vary, exhibiting diverse molecular mechanisms and epigenetic alterations.

Epigenetic regulatory mechanisms in diabetes

The present review focused on the direct epigenetic effects of hyperglycemia, it is crucial to acknowledge the inherent complexity of diabetes as a metabolic disorder. Epigenetic alterations observed in clinical and preclinical studies are likely attributable to the synergistic effects of the diabetic environment, encompassing hyperglycemia, insulin resistance, dyslipidaemia and elevated levels of advanced glycation end products. The epigenetic modifications observed in patients with diabetes or animal models are therefore the result of a concerted action of these multiple factors. Although in vitro studies using high-glucose treatment can isolate the effects of hyperglycemia, translating these findings to the in vivo context requires caution. Future mechanistic studies should aim to dissect the individual and synergistic contributions of each metabolic abnormality to the overall epigenetic landscape.

Abnormal glucose metabolism is a hallmark feature of diabetes patients. The effects of a high-sugar environment on the epigenetics of diabetes patients include abnormal DNA methylation (see High glucose and cellular DNA methylation), disruption of histone modification homeostasis (see Histone modifications in high-sugar environments) and disordered non-coding RNA regulatory networks (see Effects of high-glucose environment on non-coding RNA expression and consequences). The effect of hyperglycemic symptoms on pancreatic function in patients with diabetes (see Epigenetic regulation of pancreatic islet cells by high glucose) primarily involves the regulation of transcription factors and signaling pathways. These aspects will not be elaborated upon further here. It is particularly worth noting that epigenetic alterations are often closely associated with nutritional metabolism (115-117). Jiang et al (118) first revealed that hypermethylation of the CpG island in the promoter region of hepatic glycogen synthase kinase β (GSK-β) suppresses transcription of this gene. By activating the downstream PI3K-Akt pathway, this leads to reduced hepatic glycogen synthesis capacity and elevated fasting blood glucose levels. This epigenetic regulatory mechanism has been demonstrated to be markedly associated with the development of T2DM. In subsequent studies, the team further discovered in a high-fat diet-induced obese mouse model that liver GSK-β promoter methylation levels in the experimental group were 2.3 times higher than in the control group, accompanied by a 68% decrease in GSK-β mRNA expression. This abnormal methylation positively correlated with the insulin resistance index, suggesting that nutritional metabolic stress can exacerbate diabetes progression through epigenetic reprogramming (117,118).

Epigenetic regulation of CVD by high sugar

In modern societies, dietary shifts have led to markedly increased sugar intake. This high-sugar diet not only affects metabolism but also induces CVD through epigenetic alterations (119). Research indicates that hyperglycemia is a major CVD risk factor (120-122). Hyperglycemia not only directly causes vascular damage but also accelerates CVD progression through multiple pathways. For instance, persistent hyperglycemia leads to atherosclerosis, increased inflammatory responses and impaired vascular endothelial function: All key pathological features of CVD (123).

A high-sugar environment can induce a series of gene expression changes through epigenetic regulation, thereby affecting cardiovascular system function. Under hyperglycemic conditions, the expression levels of genes encoding NF-κB subunits (such as RELA and NFKB1) and the SOD2 gene increase in cardiomyocytes. This may be associated with the demethylation of specific CpG islands in the promoter regions of these genes. This epigenetic regulation may lead to enhanced NF-κB-mediated inflammatory responses and oxidative stress imbalance, subsequently triggering cardiomyocyte dysfunction and promoting atherosclerosis progression (122,123). Hao et al (124) observed increased H3K4me3 levels in the Smad3 gene promoter region during their study of cardiomyocytes from patients with diabetes. Smad3, a key regulator of myocardial fibrosis, undergoes methylation that leads to either overexpression or silencing of SOD2, inducing cardiovascular dysfunction. Hyperglycemia also affects the expression of non-coding RNAs (such as miRNAs), playing crucial roles in CVD pathogenesis (125). Specific miRNAs influence cardiomyocyte proliferation, apoptosis and inflammatory responses by regulating target gene expression. Studies indicate that miR-1 expression is suppressed in cardiomyocytes under high-sugar conditions, while its appropriate expression can prevent diabetic-induced cellular oxidative damage (126). Furthermore, altered expression of miR-21 and miR-208 is implicated in high-sugar-induced cardiac hypertrophy and dysfunction (127). High-sugar-induced epigenetic changes also elevate inflammatory cytokine expression in endothelial cells, thereby promoting atherosclerosis formation. Overexpression of inflammatory factors damages vascular endothelium, further exacerbating CVD risk (128). A high-sugar environment also induces epigenetic alterations in vascular smooth muscle cells (VSMCs), such as abnormal methylation of the tet methylcytosine dioxygenase 2 gene, which drives phenotypic shifts in VSMCs. This promotes cell proliferation and migration, leading to vascular narrowing and dysfunction (129).

Epigenetic regulation of kidney disease by high sugar

DKD is one of the common complications in patients with diabetes, primarily manifested as declining renal function that may ultimately lead to renal failure (130). Increasing evidence indicates that epigenetic regulation plays a crucial role in the onset and progression of DKD (131). In DKD, abnormal DNA methylation patterns have been found to be closely associated with functional impairment of renal cells (115,132). For instance, Chen et al (133) discovered markedly upregulated methylation of Annexin A2 (ANXA2) in patients with DKD, leading to disruption of podocyte cytoskeletal structures, increased renal cell apoptosis and detachment and subsequent impairment of the glomerular filtration barrier, resulting in reduced renal function (133). Studies indicate that in diabetic kidney tissue, DNMTs mediate hypermethylation of COL1A2, which activates TGF-β1, IL-6, TNF-α and IL-1β, exacerbating renal inflammation and fibrosis. This disrupts extracellular matrix (ECM) structure and releases damage-associated molecular patterns, such as fragmented collagen peptides, thereby perpetuating the inflammatory response (134,135). Methylation may also impair transcription factor binding capacity. Certain transcription factors require binding to unmethylated DNA to function and this binding may be inhibited in DKD. As noted by Bechtel et al (136), hypermethylation of RASAL1 in patients with DKD promotes Ras gene activation in fibroblasts, preventing its activation of GAP and consequently accelerating renal fibrosis. Certain genes promoting cell proliferation and fibrosis may exhibit hyperacetylation in diabetic kidneys, thereby driving pathological processes (137-139). For instance, Lazar et al (140) found that activation of the histone acetyltransferase p300/CBP in diabetic mouse kidneys enhanced ROS production and promoted renal inflammation. Briest et al (141) also revealed that under high-glucose conditions, KDM6A, acting as a histone demethylase, reduces H3K27me3 levels and accelerates glomerular inflammation progression.

Certain miRNAs and lncRNAs are up- or downregulated in patients with DKD, affecting the expression of genes associated with kidney injury (142). For example, miR-21 has been demonstrated to be upregulated in DKD. miR-21 suppresses PTEN expression by directly binding to its 3'-UTR region. PTEN serves as a negative regulator of the PI3K/Akt/mTOR signaling pathway; its downregulation leads to enhanced Akt phosphorylation, activating the downstream mTOR pathway. The activated Akt/mTOR pathway further stimulates TGF-β1 secretion, inducing EMT in renal tubular epithelial cells and promoting ECM deposition (such as type I collagen, fibronectin), thereby facilitating tubular cell proliferation and fibrosis (143-145). As noted by Sur et al (146), in high-glucose-treated renal cells, hypermethylation of the miRNA-29b promoter region and enhanced DNMT3B activity elevate promoter methylation levels of anti-fibrotic genes (such as TIMP3, MMP9), silencing their expression. This epigenetic dysregulation exacerbates glomerular fibrosis in patients with DKD. lncRNAs also play a crucial role in DKD progression. For instance, Dieter et al (147) discovered that PVT1 expression increases in high-glucose-induced human glomerular mesangial cells, accompanied by significant elevations in levels of major ECM fibronectin and type IV collagen α1, as well as TGF-β1 and plasminogen activator inhibitor-1 (PAI-1), thereby inducing renal inflammatory responses and glomerular mesangial cell apoptosis.

Fig. 1 summarizes the correlations between various epigenetic variations (primarily DNA methylation, histone modification and non-coding RNA expression) and different tissue/organ damage and diseases under high-sugar/diabetic/ hyperglycemic conditions (148).

Figure 1 Correlations between distinct epigenetic variations and tissue/organ damage and disease under conditions of high sugar intake, diabetes and hyperglycemia. Igf2, insulin-like growth factor 2; H19, imprinted maternally expressed transcript; PDX1, pancreatic and duodenal homeobox 1; PDE7B, phosphodiesterase 7B; lincIRS2, a long intergenic non-coding RNA that regulates insulin receptor substrate 2; TET, ten-eleven translocation methylcytosine dioxygenase; SIRT1, sirtuin 1; JMJD1C, jumonji domain-containing protein 1C; SOD2, superoxide dismutase 2; Smad3, mothers against decapentaplegic homolog 3; COL1A2, collagen type I alpha 2 chain; RASAL1, ras protein activator like 1; KDM6A, lysine demethylase 6A.

Epigenetically regulated therapeutics for high-sugar-induced diseases

The reversibility of epigenetic marks transforms them from mere diagnostic indicators into promising therapeutic targets in modern medicine. Their role is particularly significant in various metabolic diseases such as diabetes, cancer and CVD (149-153). Since epigenetic markers reflect cellular states under specific environmental conditions, they are considered potential disease diagnostic indicators (154,155). Epigenetic markers can be used for early screening of various diseases, providing earlier warning signals than traditional methods. For instance, methylation of MALAT1 is commonly observed in patients with diabetes, enabling its clinical application for early diagnosis (156). Epigenetic markers also facilitate disease progression monitoring and treatment response assessment. By periodically analyzing patients' epigenetic profiles, clinicians can improve the evaluation of disease progression and adjust treatment strategies as needed (157). Epigenetic characteristics further support prognostic evaluation, as certain markers directly correlate with disease outcomes. For example, in patients with diabetes, elevated GLP-1R methylation risk correlates with increased complication risk, providing a basis for personalized treatment (158). Regarding epigenetic regulation-based therapies for diabetes and related diseases, Liu et al (134) detailed therapeutic approaches for DKD. The present study primarily supplemented how epigenetics can be used to treat diabetes and its associated CVD.

Epigenetic changes are reversible, thus offering new possibilities for diabetes treatment. Researchers are exploring strategies to reverse diabetes and its complications through epigenetic therapies. This includes utilizing small-molecule drugs or gene editing technologies to modulate epigenetic marks, thereby restoring normal gene expression patterns (159,160). Such modulation can be achieved through several key mechanisms, including: i) DNA methylation regulation: Hyperglycemia can cause abnormal methylation in key genes, such as those involved in insulin signaling pathways (such as the PIK3R1 promoter region), affecting insulin secretion and sensitivity (161). For instance, inhibiting DNMTs can reverse abnormal methylation in certain genes, restore β-cell function and improve insulin resistance. 5-Aza-cytidine (5-AzaC), a chemical inhibitor, suppresses DNMT activity (162). Filip et al (163) shows that treating diabetic mouse models with 5-AzaC restores expression of key insulin secretion genes (such as Ins1 and Ins2), thereby improving β-cell function and lowering blood glucose levels. ii) Histone modification intervention: Reduced histone acetylation correlates with insulin resistance. Histone deacetylase inhibitors (HDACi), such as sodium valproate, increase histone acetylation, promote GLUT4 gene expression and improve glucose metabolism (164). iii) Non-coding RNA regulation: miRNAs (such as miR-29, miR-375) exhibit abnormal expression in diabetes, targeting insulin secretion and inflammatory responses. Modulating their levels via antisense oligonucleotides or miRNA mimics improves pancreatic function and reduces β-cell apoptosis. For example, miR-34a is a known miRNA associated with β-cell apoptosis. Research from Wang et al (165) indicates that using miR-34a inhibitors (such as antisense oligonucleotides) effectively reduces miR-34a expression. This suppression increases insulin secretion in β-cells and reduces cell apoptosis, thereby improving β-cell survival and function (165).

Epigenetic interventions offer a novel perspective for CVD therapy and their potential is exemplified by the following approaches: i) Regulation of vascular inflammation and metabolic memory: Hyperglycemia-induced 'metabolic memory' leads to persistent vascular inflammation through epigenetic mechanisms (such as sustained DNA methylation or histone modifications). Inhibiting DNMTs or HDACs can reduce inflammatory responses in vascular endothelial cells and delay atherosclerosis progression. ii) Myocardial fibrosis and cardiac remodeling: In diabetic cardiomyopathy, abnormal methylation or histone modifications of pro-fibrotic genes such as TGF-β drive myocardial fibrosis. Epigenetic drugs (such as HDACi) suppress fibrosis-related gene expression, improving cardiac function. Vorinostat, an FDA-approved HDAC inhibitor, has been shown to suppress expression of type I and III collagen genes (such as COL1A1 and COL3A1) and improve cardiovascular function by modulating fibrosis-related signaling pathways (such as the TGF-β pathway) (166). iii) Endothelial function repair: non-coding RNAs (such as lncRNA MALAT1) play regulatory roles in endothelial cell injury. Studies indicate that inhibiting MALAT1 expression enhances survival capacity in human microvascular endothelial cells and reduces apoptosis induced by hyperglycemia or oxidative stress. Research indicates that MALAT1 regulates the expression of miR-199a-5p target genes, phosphatase and vesicle-associated genes (such as RAP1A and RAP1B), by competing for binding. Targeting MALAT1 increases miR-199a-5p expression, thereby promoting endothelial functional recovery and reducing inflammation and thrombosis (167). Table IV illustrates the progress of drugs targeting epigenetic regulation for treating diseases induced by hyperglycemia (161,162,164-167).

Table IV Therapeutic progress.

Table IV

Therapeutic progress.

A, DNA methylation
Authors, year	Epigenetic Target	Therapeutic strategy	Research status	Clinical application prospects	(Refs.)
Chen et al, 2020	DNMTs	DNMT inhibitors (such as 5-Aza-cytidine)	Animal models of diabetes:diabetes mice	Potential for reversing metabolic memory	(162)
Asano et al, 2007	PIK3R1 promoter	Targeted demethylation	In vitro studies; endothelial cells	Restoring insulin signaling	(161)
B, Histone modifications
Özel et al, 2021	HDACs	HDAC inhibitors (such as Vorinostat, Sodium Valproate)	Some have already in Animal models; some have in clinical trials	Improving insulin sensitivity, reducing fibrosis	(166)
Thakur et al, 2024	HATs (p300/CBP)	HAT inhibitors	Preclinical studies in diabetic nephropathy	Attenuating renal inflammation and fibrosis	(164)
C, Non-coding RNAs
Wang et al, 2022	miR-34a	Antisense oligonucleotides (inhibitors)	In vitro and animal models: in liver tissues of db/db mice	Protecting β-cells from apoptosis	(165)
Samidurai et al, 2023	lncRNA MALAT1	siRNA, ASO-mediated knockdown	In vitro cell and animal models of vascular dysfunction	Improving endothelial function	(167)
Wang et al, 2022	Circulating miRNAs (such as miR-21)	As diagnostic/prognostic biomarkers	Clinical association studies	Non-invasive monitoring of DKD progression (requires standardization)	(165)

[i] DNMT, DNA methyltransferase; PIK3R1, phosphoinositide-3-kinase regulatory subunit 1; HDAC, histone deacetylase; HAT, histone acetyltransferase.

Perspective

The epigenetic regulatory mechanisms triggered by high-sugar environments (including hyperglycemia, or high glucose treatment) are increasingly becoming a research focus to elucidate the pathogenesis of diabetes and its complications (such as cardiovascular disease, nephropathy and neuropathy). In clinic, hyperglycemia not only alters cellular metabolic states but also induces persistent changes in cellular function by affecting multiple epigenetic modifications, including DNA methylation, histone modifications and non-coding RNA expression. Hyperglycemia-induced epigenetic variations trigger functional alterations across multiple organs and precipitate diverse diseases. The present review highlighted only well-researched cellular, organ and disease models; numerous other disease models, such as diabetic retinopathy and diabetic foot, due to the scarcity of research materials, remain incompletely elucidated.

Despite the abundance of existing research on epigenetic alterations in high-sugar environments and diabetes (including its complications), numerous uncharted territories warrant further exploration. It is therefore recommend to strengthen research in the following three areas: i) Mechanistic studies: Deepening our understanding of the specific roles played by different epigenetic mechanisms in diabetes pathogenesis. For instance, analyzing the epigenetic characteristics of vascular cells in patients with diabetes via high-throughput sequencing techniques. ii) Intervention strategy research: Investigating how various environmental factors (such as diet and exercise) influence epigenetic alterations. iii) Epigenetics and metabolic disease association studies: Further exploring the links between epigenetic modifications and other metabolic disorders to uncover broader biological mechanisms.

Regarding the application of epigenetics tools for disease diagnosis and treatment, the following areas warrant greater emphasis: i) Therapeutic strategies targeting epigenetic modifications: Developing drugs and tools (such as CRISPR/Cas9-based modification tools) that target specific epigenetic markers to restore normal cellular function; ii) Application of personalized medicine: Analyzing patients' epigenetic profiles to formulate tailored treatment plans, which holds promise for enhancing therapeutic outcomes; Changes in epigenetic markers under hyperglycemic conditions carry significant implications for disease diagnosis and monitoring. As research progresses, these markers may emerge as a new generation of diagnostic indicators, providing clinicians with more sensitive and specific detection methods, ultimately improving patient treatment outcomes and quality of life.

Availability of data and materials

Not applicable.

Authors' contributions

DY and WW contributed to the conception and design of the article. HZ drafted the manuscript. XL and YL revised the manuscript. Data authentication is not applicable. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Abbreviations:

Acknowledgments

Not applicable.

Funding

The present study was supported by Jilin Provincial Health Talent Program (grant no. JLSWSRCZX2025 to WW).

References