Epigenetic Mechanisms Linking COVID-19 and Diabetes: Implications for Metabolic Health

The COVID-19 pandemic has had a profound effect on global health, revealing vulnerabilities in various populations, especially those with pre-existing conditions like diabetes [1-3]. Since its emergence in late 2019, the novel coronavirus SARS-CoV-2 has caused millions of infections and deaths during the pandemic [4]. Individuals with diabetes face an increased risk of severe complications, as the virus can disrupt blood glucose control and increase the likelihood of diabetes-related issues, including Cardiovascular Diseases (CVDs) [1-3,5-7]. For example, a research study that included more than 61 million people in England during the first wave of the pandemic showed that, after accounting for variables like age, sex, socioeconomic status, ethnicity, and location, individuals with diabetes faced a greater risk of dying in the hospital from COVID-19 than those without the disease. The odds ratios for in-hospital mortality resulting from COVID-19, compared to the general population, were 3.51 (95% CI 3.16-3.90) in individuals with Type 1 Diabetes (T1D) and 2.03 (1.97-2.09) in those with Type 2 Diabetes (T2D) [8]. In a different study covering 39 states across the United States, there were 82,928 documented deaths attributable to diabetes from January 1 to November 3, 2020, with 62,561 of these occurrences taking place during the pandemic [9]. The heightened vulnerability leads to more serious health consequences, including extended hospitalizations and elevated rates of illness and death. The convergence of these two public health issues highlights the pressing necessity to investigate their intricate relationships. As scientists explore the connections between COVID-19 and diabetes, the role of epigenetics has emerged as a crucial focus [10-12].

Epigenetics involves inheritable changes in gene expression that occur without altering the DNA sequence itself. Modifications to the chemical structure of DNA bases and changes to chromosomal configuration can result in variations in gene expression without directly altering the genetic code [13-15]. Environmental elements, like viral infections, can lead to epigenetic modifications that influence the expression of genes related to inflammation, insulin sensitivity, and glucose metabolism [16- 18]. In the case of COVID-19, the surge of inflammatory cytokines can alter DNA methylation and histone modifications, potentially impairing the function of insulin-sensitive tissues and worsening Insulin Resistance (IR) [19-21]. Additionally, the recent Nobel Prize recognition of microRNA underscores the role of miRNA in epigenetic mechanisms as a promising avenue for treatments and a potential biomarker for those with diabetes and COVID-19 [22-25]. Moreover, the repercussions of COVID-19 extend beyond the initial illness, with emerging evidence suggesting that certain individuals experience ongoing metabolic issues long after recovery, often referred to as “long COVID” [26-28]. Symptoms of long-term COVID can include fatigue, cognitive difficulties, and lingering respiratory issues, but metabolic disturbances such as Insulin Resistance (IR) and the development of diabetes are now also being acknowledged [29-31]. The epigenetic changes that occur during the early phase of infection may result in enduring effects on the gene expression related to glucose metabolism and inflammation. Research indicates that individuals recovering from COVID-19 may exhibit lasting changes in their metabolic health, underscoring the necessity for ongoing monitoring and intervention [32].

In addition, investigating the epigenetic relationships between COVID-19, diabetes, and long COVID is vital for comprehending the underlying biological mechanisms and for informing public health initiatives and medical interventions. Insights gained from this research could result in customized treatment approaches that focus on the epigenetic changes associated with metabolic disorders. In a post-COVID landscape, it is essential to deepen our understanding of these links to safeguard the health of at-risk populations and develop strategies to mitigate the enduring impacts of the pandemic on metabolic health [32-34]. Against this backdrop, the purpose of this review is to investigate the epigenetic mechanisms that may exacerbate IR and perturb glucose metabolism in individuals with diabetes in relation to COVID-19. By synthesizing existing research, this review intends to emphasize significant epigenetic processes and their consequences for long-term metabolic health. Ultimately, it aims to improve our comprehension of the relationship between these conditions and to inform future research avenues in the field of diabetes.

The progression of COVID-19 arises from a complex interaction of multiple pathophysiological processes. In the beginning, the SARS-CoV-2 virus inflicts direct harm on host cells, resulting in cellular impairment and tissue damage [35]. This viral infection triggers a decline in Angiotensin-Converting Enzyme 2 (ACE2) levels, disrupting the balance of the Renin-Angiotensin-Aldosterone System (RAAS) [36]. As a result, levels of angiotensin II increase while the breakdown of des-Arg9-bradykinin is diminished, exacerbating vascular permeability and inflammation [37]. A significant aspect of the disease is the dysregulated immune response, often referred to as a “Cytokine Storm,” which involves an excessive release of proinflammatory cytokines that can lead to Acute Respiratory Distress Syndrome (ARDS) [38-40]. Additionally, COVID-19 is associated with coagulopathy, characterized by the release of procoagulatory factors and thrombotic microangiopathy, likely stemming from endothelial injury caused by the virus, together with activation of the complement system and cytokine effects, resulting in localized and systemic “immunothrombosis” [41,42].

This term describes the interplay between the body’s innate immune response and the coagulation mechanism-especially within the microvasculature, where dysfunction of endothelial cells leads to increased clot formation and inflammation. Also, some individuals might develop autoimmune responses, wherein the immune system mistakenly attacks the body’s own tissues, complicating the clinical presentation [43-45]. Collectively, these mechanisms underscore the complex nature of COVID-19 pathology, which contributes to severe outcomes for those affected. These outcomes include significant metabolic disturbances, particularly impacting glucose metabolism, insulin sensitivity, and lipid profiles. These alterations can have profound implications for patient outcomes and the management of pre-existing metabolic conditions such as diabetes, highlighting the critical need for comprehensive approaches in treating COVID-19 patients. To expand on this, studies indicate that COVID-19 can lead to notable alterations in glucose metabolism, with numerous hospitalized individuals displaying elevated blood glucose levels, even if they have no previous history of diabetes [46,47]. Specifically, heightened blood glucose has frequently been seen in patients with severe COVID-19 cases and is associated with poorer clinical outcomes [48,49].

For instance, a research study conducted in Wuhan focused on hospitalized COVID-19 patients, primarily among the older demographic, and found that 21.6% had a prior diagnosis of diabetes. Notably, when evaluating the initial glucose measurements at the time of their admission, it was found that 20.8% of these patients were newly diagnosed with diabetes, as indicated by fasting blood glucose levels of 7.0 mmol/L or above or an HbA1c level of 6.5% or higher. Furthermore, the study revealed that 28.4% of the patients showed signs of dysglycemia, defined by fasting glucose levels between 5.6 and 6.9 mmol/L, or HbA1c levels ranging from 5.7% to 6.4% [46].

Several factors lead to higher blood glucose levels in many patients with COVID-19. Initially, the inflammatory response initiated by the virus can lead to Insulin Resistance (IR) as proinflammatory cytokines disrupt insulin signaling pathways [50,51]. Additionally, the physiological stress caused by the infection raises levels of cortisol and catecholamines, both of which enhance gluconeogenesis and glycogenolysis, worsening hyperglycemia [52,53]. The relationship between COVID-19 and IR is notably important. Studies indicate that severe cases of COVID-19 can exacerbate IR, resulting in metabolic complications [54,55]. Individuals with acute COVID-19 frequently show a significant decline in insulin sensitivity, and this impact may persist even after the initial infection phase has ended [56].

Various factors play a role in the exacerbating IR associated with COVID-19. Intense inflammation, whether stemming from preexisting metabolic disorders or the COVID-19 infection itself, can increase IR, thereby worsening dysglycemia in individuals with diabetes and intensifying the severity of COVID-19 [3-5,46-48]. Furthermore, the endothelial dysfunction induced by the virus can impede glucose absorption and utilization in peripheral tissues, thereby further aggravating IR [57,58]. Moreover, COVID-19 is associated with significant alterations in lipid metabolism. Studies indicate that patients often exhibit dyslipidemia, marked by increased triglycerides and modified cholesterol levels [59,60]. Specifically, numerous individuals infected with COVID-19 show elevated triglyceride levels and reduced High-Density Lipoprotein (HDL) cholesterol, both of which are contributors to CVD risk [61,62]. The alterations in lipid profiles can be linked to a variety of factors. A significant factor is the influence of inflammatory mediators; elevated levels of inflammatory cytokines can interfere with liver lipid metabolism, resulting in the buildup of triglycerides in the liver [63,64]. Moreover, endothelial dysfunction and the related inflammatory response can hinder the removal of lipoproteins, worsening dyslipidemia [65,66]. Importantly, elevated levels of blood glucose can promote the spread of SARSCoV- 2, creating a vicious cycle [67,68]. Research has shown that high glucose levels in human monocytes can increase the virus’s replication, with glycolysis further enhancing this effect [69]. Thus, higher blood glucose may support viral growth. Additionally, evidence indicates that hyperglycemia, along with a history of T1D and T2D, acts as an independent factor associated with increased morbidity and mortality in people infected with SARS [70,71]. Collectively, these studies offer significant evidence that connects COVID-19 with the development of diabetes, which impacts metabolic health. Nonetheless, addressing all the evidence that ties these two conditions is beyond the scope and focus of this narrative review.

SARS-CoV-2 skillfully exploits the metabolic processes and transcription systems of host cells to enhance its replication and ensure successful infection. An essential part of this strategy involves the virus’s ability to modify the host’s gene expression by managing essential gene transcription, adjusting chromatin dynamics, and influencing microRNA (miRNA) pathways [12,15,16,18,19]. Research indicates that the SARS-CoV-2 protein encoded by the ORF8 gene acts as a histone mimic, specifically replicating the ARKS (Ala-Arg-Lys-Ser) motif found in histone H3. This mimicry allows ORF8 to disrupt the epigenetic regulation of host cells. ORF8 interacts with chromatin, hindering the regulation of key Post-Translational Modifications (PTMs) of histones and leading to chromatin compaction [72]. Consequently, this disruption affects the accessibility of the genome, which in turn influences gene expression and the host’s immune response. Eliminating either the ORF8 gene or the particular histone mimic site markedly decreases SARS-CoV-2’s capacity to perturb the chromatin of host cells. This disruption plays a vital role in altering the transcriptional response to infection [72]. Therefore, such deletions also result in a reduction in the quantity of viral genomes produced. Essentially, by impeding these components, the virus is less capable of manipulating the host’s epigenetic landscape, which is crucial for its replication and longevity.

Additionally, when SARS-CoV-2 infects a host, it triggers various epigenetic modifications in the host’s cells, which notably affect the immune response [12,15,16,18,19,73]. Such alterations may activate pathways that create an antiviral setting, allowing the host to express Interferon-Stimulated Genes (ISGs) and additional immune-related components that bolster defenses against viral replication [74,75]. Fang et al. examined the link between levels of Histone 3-Lysine 9 Dimethylation (H3K9me2) and Interferon (IFN) expression in vitro. H3K9me2 is a repressive histone modification essential for regulating DNA methylation and the establishment of heterochromatin [76]. This specific modification prevents acetylation by recruiting members of the Heterochromatin Protein 1 (HP1) family. In their research, the authors observe an inverse relationship between H3K9me2 levels in the promoter region of type I interferons and the expression of Interferon-Stimulated Genes (ISGs) in dendritic cells. This indicates that H3K9me2 is an important regulator of the IFN response, underscoring its role in modulating gene expression during immune reactions [77,78]. Moreover, studies show that acetylation and deacetylation of histones play a crucial role in the body’s defense against viruses [79,80]. Additional studies reveal that in SARS-CoV-2 infections, specific histone acetylation marks appear in higher concentrations at the promoters of ISGs, leading to increased gene expression [10-12,81]. This finding suggests that the host actively triggers an antiviral response through epigenetic alterations involving histones. Additionally, studies suggest that the activity of host acetyl transferases on histone acetylation significantly enhances the expression of ISGs, leading to increased production of antiviral cytokines [82,83]. Collectively, these observations highlight the important role of histone modifications in the immune response to viral infections. On the other hand, Nsp5 (Non-Structural Protein 5), a protease encoded by SARS-CoV-2, interacts with Histone Deacetylase 2 (HDAC2) [84]. This interaction hinders interferon production, which is essential for a proper antiviral immune response, resulting in heightened inflammation. Histone Deacetylases (HDACs) are crucial for gene expression regulation by functioning as transcriptional repressors; they do this by removing acetyl groups from histones, making DNA generally less accessible for transcription.

In particular, HDAC2 is significant for activating various ISGs through its association with BRD4 (Bromodomain Containing Protein 4), a protein that aids in the transcription of these antiviral genes [85]. As a result, Nsp5’s disruption of HDAC2 compromises the body’s capacity to launch an effective antiviral response, underscoring the role of this protease in the pathogenicity of SARSCoV- 2 [86]. Furthermore, SARS-CoV-2 has the potential to impact the activity and role of specific miRNAs, potentially modifying the host’s immune response by targeting antiviral genes for degradation or inhibiting their translation [87,88]. This interference reduces the host’s ability to react efficiently to the infection, allowing the virus to evade immune detection and replicate with greater ease. For example, evidence shows that miR-21 is greatly increased in the body during SARS-CoV-2 infection [89,90]. The rise in miR-21 leads to immune evasion by degrading different antiviral genes through targeting [91,92]. Moreover, an expanding collection of studies further suggests that host miRNAs are vital in the infection and replication of SARS-CoV-2. Importantly, viral miRNAs can notably modify the host’s transcriptome [93-95]. Several miRNAs play a crucial role in the function of different immune cell types and are essential for the maintenance of immune balance in the host.

Hence, considering their significant impact on host-pathogen interactions during infections, miRNAs could serve as valuable targets for developing antiviral therapies. Intensifying, in a review authored by Nahid Arghiani et al., the authors present a comprehensive table listing host miRNAs and their specific targets related to SARS-CoV-2 [95]. This compilation underscores the interactions between viral and host miRNAs, highlighting the potential of these small molecules as therapeutic targets to fight COVID-19. Together, the complex interplay between SARS-CoV-2 and the host’s epigenetic landscape, particularly the involvement of miRNAs, highlights the ongoing battle between the virus’s adaptation strategies and the host’s immune defenses, as well as other epigenetic mechanisms. A deeper understanding of these processes will offer crucial insights into potential therapeutic targets and the wider implications of viral infections on the host’s cellular regulation. In essence, this section lays the groundwork for exploring the impact of these interactions on diabetes, which will be further discussed in the next section.

Recent studies highlight a significant link between COVID- 19-induced epigenetic changes and the development of diabetes, primarily focusing on disruptions in glucose metabolism, chronic inflammation, and β-cell function [96-98]. For instance, altered DNA methylation patterns in individuals with COVID-19 are associated with IR, particularly affecting key genes like IRS1 (Insulin Receptor Substrate 1) and GLUT4 that are critical for glucose uptake [99,100]. Furthermore, SARS-CoV-2 infection can hijack cellular mechanisms, influencing metabolic pathways such as the PI3K/Akt (phosphoinositide 3-kinase/protein kinase B) pathway, which is essential for glucose metabolism, resulting in impaired insulin signaling and increased gluconeogenesis [101- 103]. COVID-19 exacerbates chronic inflammation, a known risk factor for T2D, through a “cytokine storm,” which is characterized by an overproduction of pro-inflammatory cytokines like IL-6 (interleukin-6) and TNF-α (Tumor Necrosis Factor-Alpha) [104,105]. These cytokines can induce epigenetic changes in target cells, leading to a sustained inflammatory state that promotes IR. Research has shown that COVID-19 alters the epigenetic landscape of immune cells, enhancing the expression of inflammatory mediators, further complicating metabolic health [106,107].

Additionally, emerging evidence suggests that ACE2 (Angiotensin-Converting Enzyme 2), the receptor for SARSCoV- 2, may be expressed in pancreatic β-cells and is subject to epigenetic regulation [108,109]. This presence raises concerns, as ACE2’s expression could impact the vulnerability of β-cells to viral infection and subsequent dysregulation. Epigenetic changes that impact the expression of key transcription factors involved in insulin production, such as PDX1 (Pancreatic And Duodenal Homeobox 1) and MAFA (a basic leucine zipper transcription factor), can result in decreased insulin secretion in response to glucose [110-112]. The inflammatory environment induced by the SARS-CoV-2 can also trigger apoptosis in β-cells, with elevated cytokine levels promoting the expression of pro-apoptotic genes through epigenetic mechanisms, resulting in β-cell loss [113- 115]. Moreover, alterations in the signaling pathways essential for Glucose-Stimulated Insulin Secretion (GSIS) affect genes involved in calcium signaling and exocytosis, contributing to impaired insulin secretion [116-118]. In addition, the investigation of anti-aging genes has become more essential in comprehending the worldwide increase in chronic illnesses [119-124]. One notable gene, Sirtuin 1 (Sirt1), holds an important role in enhancing the immune system. Sirt1 is an NAD+-dependent protein deacetylase that manages the function of nuclear receptors and is critical for both insulin sensitivity and immune performance [125,126].

When Sirt1 is compromised, it can speed up the onset of ailments like Non-Alcoholic Fatty Liver Disease (NAFLD), obesity, diabetes, and Neurodegenerative Disorders (NDs) [127-131]. Considering its involvement in controlling insulin resistance and immune reactions, it is reasonable to speculate that Sirt1 malfunctions could be a major contributor to the severity of COVID-19, especially in individuals with diabetes, by hindering the innate immune response. A particularly severe consequence of COVID-19 infection is the disruption of Sirt1’s role in mitochondrial function [132,133]. This impairment exacerbates the disease by promoting mitochondrial dysfunction, mitophagy, and ultimately, cell death. In this context, preserving Sirt1 function may offer therapeutic potential in mitigating some of the most damaging effects of COVID-19, especially for vulnerable populations [134,135].

Recent advancements in aging research highlight that agingrelated pathways not only influence lifespan but also have a significant impact on health span, particularly through their effect on the aging immune system [122-124]. Both cellular senescence and aging are now recognized as central factors in the pathogenesis of COVID-19 [136]. Given the critical role of Sirt1 in aging, it is reasonable to suggest that maintaining its function could help reduce the cellular senescence triggered by COVID-19, particularly in individuals with diabetes, and potentially alleviate some of the disease’s more severe outcomes. Furthermore, studies suggest that Sirt1 might function as an important diagnostic marker for chronic illnesses and could provide insights for potential treatment options [126-130]. Proteomic profiling, which entails evaluating plasma Sirt1 levels and examining related proteins, is important for determining the severity of conditions like cardiovascular disease, NAFLD, diabetes, and NDs. These evaluations offer valuable information on the advancement of diseases and can assist in shaping treatment approaches.

Overall, the accumulating evidence underscores a multifaceted relationship between COVID-19-induced epigenetic changes and the emergence of diabetes, affecting glucose metabolism, inflammatory responses, and β-cell functionality. Understanding these intricate pathways is crucial for addressing the long-term implications of COVID-19 and developing targeted therapeutic strategies to mitigate diabetes risk in affected individuals. Continued research in this area remains essential for clarifying these connections and informing effective interventions. Additionally, research indicates that individuals with long COVID frequently show symptoms that may be associated with changes to gene expression through epigenetic modifications, impacting inflammation, oxidative stress, and metabolic regulation [137,138]. For instance, research demonstrates that inflammatory cytokines have the ability to cause epigenetic modifications in immune and metabolic genes, leading to persistent inflammation that disturbs balance within the body and leads to IR [139,140]. More importantly, the potential role of ACE2 in long-term COVID is significant, as continued expression of this receptor in various tissues may facilitate ongoing dysregulation of metabolic processes [141,142].

This dysregulation, combined with the cumulative effects of epigenetic changes, may heighten the risk of developing diabetes and other metabolic disorders in individuals experiencing long COVID [143]. Further studies are necessary to establish a strong connection between SARS-CoV-2 and long COVID. Together, the evidence illustrates a strong and complex connection between epigenetic changes caused by COVID-19 and the onset of diabetes, profoundly impacting glucose metabolism, inflammatory pathways, and β-cell function. Moreover, the possible links between long COVID and epigenetic changes emphasize the importance of more thorough studies on the lasting effects of COVID-19 on metabolic health. Ongoing investigation in this field is crucial to understanding these correlations and advising successful interventions.

In concert, the interaction among COVID-19, diabetes, and epigenetic alterations highlights a complex and significant public health dilemma. Infection with SARS-CoV-2 not only exacerbates Insulin Resistance (IR) and impacts glucose metabolism but also induces persistent alterations to epigenetics that may elevate the susceptibility to diabetes, especially in vulnerable populations. The continual inflammation and alterations in β-cell function introduce a higher level of complexity to metabolic health outcomes. Comprehending these intricate mechanisms is essential for developing accurate treatment plans and public health interventions to mitigate the long-term effects of COVID-19 on metabolic disorders. Continuing research will be essential for gaining insights into these relationships and safeguarding the well-being of affected individuals, particularly as we navigate the aftermath of the pandemic. Future studies need to thoroughly investigate the significant gaps in our knowledge of the lasting impacts of COVID-19 on epigenetic changes, especially how they affect chronic illnesses like diabetes. An important focus of study is whether certain changes in the host genome’s epigenetics contribute to the development of long COVID in impacted individuals. Furthermore, it is crucial to determine if these epigenetic changes can lead to autoimmune conditions such as T1D. In order to investigate these urgent inquiries, it is crucial to conduct thorough long-term research on individuals recovering from COVID-19 to monitor changes in epigenetics over time and how they relate to the development of diabetes.

Utilizing Epigenome-Wide Association Studies (EWAS) can help pinpoint particular epigenetic markers linked to both COVID-19 and diabetes, shedding light on variations in methylation patterns and chromatin remodeling processes. Additionally, combining these results with transcriptomic and metabolomic data will offer a complete insight into the biological processes affected by SARSCoV- 2. Finally, it is essential to strengthen strong connections between basic research and clinical environments, which includes forming partnerships for patient recruitment, creating platforms to share electronic data, and working with policymakers to incorporate research findings into public health recommendations. This thorough method will greatly improve our comprehension of the complex interaction among COVID-19, diabetes, and epigenetic processes, ultimately guiding new approaches for preventing and treating these conditions.

This research is funded by an intramural grant from Bandhan, India.

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