Type-2 diabetes is a systemic condition with rising global prevalence, disproportionately affecting Indigenous communities worldwide. Recent advances in epigenomics methods, particularly in DNA methylation detection, have enabled the discovery of associations between epigenetic changes and Type-2 diabetes. In this review, we summarise DNA methylation profiling methods, and discuss how these technologies can facilitate the discovery of epigenomic biomarkers for Type-2 diabetes. We critically evaluate previous DNA methylation biomarker studies, particularly those using microarray platforms, and advocate for a shift towards sequencing-based approaches to improve genome-wide coverage. Furthermore, we emphasise the need for biomarker studies that include genetically diverse populations, especially Indigenous communities who are significantly impacted by Type-2 diabetes. We discuss research approaches and ethical considerations that can better facilitate Type-2 diabetes biomarker development to ensure that future genomics-based precision medicine efforts deliver equitable health outcomes. We propose that by addressing these gaps, future research can better capture the genetic and environmental complexities of Type-2 diabetes among populations at disproportionate levels of risk, ultimately leading to more effective diagnostic and therapeutic strategies.

The prevalence of type 2 diabetes (T2D) has increased significantly over the past three decades, with an estimated 30-40% of cases remaining undiagnosed. Brown and beige adipose tissues are known for their remarkable catabolic capacity, and their ability to diminish blood glucose plasma concentration. Beige adipose tissue can be differentiated from adipose-derived stem cells or through transdifferentiation from white adipocytes. However, the impact of T2D progression on beige adipocytes' functional capacity remains unclear. Transcriptomic profiling of subcutaneous adipose tissue biopsies from healthy normal-weight, obese, prediabetic obese, and obese subjects diagnosed with T2D, reveals a progressive alteration in cellular processes associated with catabolic metabolism, circadian rhythms, thermogenesis-related signaling pathways, cellular stress, and inflammation. MAX is a potential transcription factor that links inflammation with the circadian clock and thermogenesis during the progression of T2D. This study unveils an unrecognized transcriptional circuit that increasingly disrupts subcutaneous adipose tissue oxidative capacity during the progression of T2D. These findings could open new research venues for developing chrono-pharmaceutical strategies to treat and prevent T2D.

Impaired insulin secretion contributes to the pathogenesis of type 1 diabetes mellitus through autoimmune destruction of pancreatic β-cells and the pathogenesis of severe forms of type 2 diabetes mellitus through β-cell dedifferentiation and other mechanisms. Replenishment of malfunctioning β-cells via islet transplantation has the potential to induce long-term glycemic control in the body. However, this treatment option cannot widely be implemented in clinical due to healthy islet donor shortage. Emerging β-cell replacement with human-induced pluripotent stem cell (iPSC) provides high remedial therapy hopes. Thus, tremendous progress has been made in developing β-cell differentiation protocols in vitro; however, most of the differentiated iPSC-derived β-cells showed immature phenotypes associated with low efficiency depending on the iPSC lines used, creating a crucial barrier for their clinical implementation. Multiple mechanisms including differences in genetic, cell cycle patterns, and mitochondrial dysfunction underlie the defective differentiation propensity of iPSC into insulin-producing β-cells. Accumulating evidence recently indicated that, following the reprogramming, epigenetic memory inherited from parental cells substantially affects the differentiation capacity of many iPSC lines. Therefore, differences in epigenetic signature are likely to be essential contributing factors influencing the propensity of iPSC differentiation. In this review, we will document the impact of the epigenome on the reprogramming efficacy and differentiation potential of iPSCs and how targeting the epigenetic residual memory could be an additional strategy to improve the differentiation efficiency of existing protocols to generate fully functional hPSC-derived pancreatic β-cells for diabetes therapy and drug screening.

Breast cancer (BC) is a multifaceted disease distinguished by a range of molecular subtypes and varying clinical prognoses. The involvement of DNA methylation in the dysregulation of gene expression has been linked to the development and progression of BC. Therefore, this study aimed to investigate the association between ANGPT1 gene expression and DNA methylation in BC patients. Eight Saudi female blood samples were used to undergo for whole genome bisulfite sequencing (WGBS) and RNA sequencing for the identification of novel DNA methylation targets. Several public domain BC datasets including the METABRIC cohort, TCGA, and Kaplan Meier Plotter datasets, were used to explore the prognostic significance of ANGPT1 gene. Then, the demethylation agent 5-aza-2'-deoxycytidine was used to examine the potential association between DNA methylation and ANGPT1 expression. Finally, the validation was conducted on blood samples from 49 Saudi females using methylight techniques. Our results shows that upregulation of ANGPT1 gene expression exhibited hypomethylation pattern in BC samples. these results were confirmed by MCF7 cell line experiments. Demethylating using 5-aza in MCF7 and MCF10A showed a high expression of ANGPT1 in both cell lines. ANGPT1 mRNA expression was found to poor prognostic biomarker and lower Breast Cancer-Specific Survival (BCSS) in BC patients. The potential importance of abnormal DNA methylation in the development and advancement of BC is significant. ANGPT1 may act as an oncogene and could be extensively studied further to behave as a predictive biomarker for breast cancer.

Numerous epidemiological studies have found that pesticide exposure is associated with the incidence of type 2 diabetes (T2D); however, the underlying mechanisms remain unknown. DNA methylation may play a role in this process.

To identify the genes associated with pesticide exposure and T2D by reviewing the current literature.

We systematically searched PubMed and Embase for relevant studies that examined the association between pesticide exposure and DNA methylation, and studies on DNA methylation and T2D through January 15, 2024.

We identified six genes (Alu, CABLES1, CDH1, PDX1, PTEN, PTPRN2) related to pesticide exposure and T2D. We also suggested future research directions to better define the role of DNA methylation in the association between pesticide exposure and T2D.

DNA methylation of specific genes may play a vital role in the association between pesticide exposure and T2D.

Dietary factors may regulate the epigenome. We aimed to explore whether a diet intervention, including excess sugar, affects the methylome in human sperm, and to describe the sperm methylome. We used Whole Genome Bisulfite Sequencing (WGBS) to analyze DNA methylation in sperm taken at three time points from 15 males during a diet intervention; i) at baseline, ii) after one week on a standardized diet, and iii) after an additional week on a high-sugar diet providing 150% of their estimated total energy expenditure.

We identified seven nominal diet-associated differentially methylated regions in sperm (p < 0.05). The diet was nominally associated with methylation of 143 sites linked to fertility (e.g. AHRR, GNAS, and HDAC4), 313 sites in imprinted genes (e.g. GLIS3, PEG10, PEG3, and SNURF), and 42 sites in top 1%-expressed genes (e.g. CHD2) (p < 0.05). In sperm, 3'UTRs and introns had the highest levels of methylation, while 5'UTRs and CpG islands had the lowest levels. Non-expressed genes in human sperm were hypomethylated in exons compared with transcribed genes.

In human sperm, DNA methylation levels were linked to gene expression, and excess sugar had modest effects on methylation on imprinted and highly expressed genes, and genes affecting fertility.

Diabetes and chronic obstructive pulmonary disease (COPD) are prominent global health challenges, each imposing significant burdens on affected individuals, healthcare systems, and society. However, the specific molecular mechanisms supporting their interrelationship have not been fully defined.

We identified the differentially expressed genes (DEGs) of COPD and diabetes from multi-center patient cohorts, respectively. Through cross-analysis, we identified the shared DEGs of COPD and diabetes, and investigated alterations of signaling pathways using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA). By using weighted gene correlation network analysis (WGCNA), key gene modules for COPD and diabetes were identified, and various machine learning algorithms were employed to identify shared biomarkers. Using xCell, we investigated the relationship between shared biomarkers and immune infiltration in diabetes and COPD. Single-cell sequencing, clinical samples, and animal models were used to confirm the robustness of shared biomarkers.

Cross-analysis identified 186 shared DEGs between diabetes and COPD patients. Functional enrichment results demonstrate that metabolic and immune-related pathways are common features altered in both diabetes and COPD patients. WGCNA identified 526 genes from key gene modules in COPD and diabetes. Multiple machine learning algorithms identified 4 shared biomarkers for COPD and diabetes, including CADPS, EDNRB, THBS4 and TMEM27. Finally, the 4 shared biomarkers were validated in single-cell sequencing data, clinical samples, and animal models, and their expression changes were consistent with the results of bioinformatic analysis.

Through comprehensive bioinformatics analysis, we revealed the potential connection between diabetes and COPD, providing a theoretical basis for exploring the common regulatory genes.

A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.

By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.

Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D. Differential expression levels of one or more predicted target relevant miRNA(s) were identified for approximately 35% of the dysregulated GSEA pathways. These include miRNAs with a significant overrepresentation of targets involved in GLUT4 translocation (miR-4643 and miR-548z), signaling by receptor tyrosine kinases pathways (miR-607), and muscle contraction (miR-4658). Acquired DNA methylation changes in skeletal muscle were quantitatively small in twins with T2D compared with the co-twins without T2D. Key methylation and expression results were validated in muscle, myotubes, and/or myoblasts from unrelated subjects with T2D and controls. Finally, mimicking T2D-associated changes by overexpressing miR-548 and miR-607 in cultured myotubes decreased expression of target genes, GLUT4 and FGFR4, respectively, and impaired insulin-stimulated phosphorylation of Akt (Ser473) and TBC1D4.

Together, we show that T2D is associated with non- and epigenetically determined differential transcriptional regulation of pathways regulating skeletal muscle metabolism and contraction.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions.

This study explores the correlation between site-specific methylation levels of the KCNJ11 promoter and type 2 diabetes mellitus (T2DM), analyzing potential molecular mechanisms.

Thirty patients newly diagnosed with T2DM and 30 healthy controls were selected to determine the CpG methylation levels in the promoter region of the KCNJ11 gene using the bisulfite assay. The online software JASPAR was used to predict transcription factors binding to differentially methylated sites. Key transcription factors were further validated through quantitative PCR (q-PCR) and chromatin immunoprecipitation followed by PCR (ChIP-PCR).

Methylation at multiple CpG sites within the KCNJ11 gene promoter was generally reduced in newly diagnosed T2DM patients compared with healthy individuals. The methylation status of CpG-471, a site crucial for the binding of the transcription factor TCF12, emerged as potentially influential in T2DM pathogenesis. This reduction in methylation at CpG-471 may enhance TCF12 binding, thereby altering KCNJ11 expression.

Hypomethylation of specific CpG sites in the promoter region of the KCNJ11 gene in patients with incipient T2DM potentially contributes to the disease's pathogenesis. This hypomethylation may influence TCF12 binding, with potential regulatory effects on KCNJ11 expression and pancreatic beta-cell function, though further studies are needed to confirm the exact mechanisms involved.

The unsustainable use of manmade chemicals poses significant threats to biodiversity and human health. Emerging evidence highlights the potential of certain chemicals to cause transgenerational impacts on metabolic health. Here, we investigate male transmitted epigenetic transgenerational effects of the anti-androgenic herbicide linuron in the pancreas of Xenopus tropicalis frogs, and their association with metabolic phenotypes. Reduced representation bisulfite sequencing (RRBS) was used to assess genome-wide DNA methylation patterns in the pancreas of adult male F2 generation ancestrally exposed to environmentally relevant linuron levels (44 ± 4.7 μg/L). We identified 1117 differentially methylated regions (DMRs) distributed across the X. tropicalis genome, revealing potential regulatory mechanisms underlying metabolic disturbances. DMRs were identified in genes crucial for pancreatic function, including calcium signalling (clstn2, cacna1d and cadps2), genes associated with type 2 diabetes (tcf7l2 and adcy5) and a biomarker for pancreatic ductal adenocarcinoma (plec). Correlation analysis revealed associations between DNA methylation levels in these genes and metabolic phenotypes, indicating epigenetic regulation of glucose metabolism. Moreover, differential methylation in genes related to histone modifications suggests alterations in the epigenetic machinery. These findings underscore the long-term consequences of environmental contamination on pancreatic function and raise concerns about the health risks associated with transgenerational effects of pesticides.

A central aspect of type 2 diabetes is decreased functional β-cell mass. The orphan nuclear receptor Nr4a1 is critical for fuel utilization, but little is known regarding its regulation and function in the β-cell. Nr4a1 expression is decreased in type 2 diabetes rodent β-cells and type 2 diabetes patient islets. We have shown that Nr4a1-deficient mice have reduced β-cell mass and that Nr4a1 knockdown impairs glucose-stimulated insulin secretion (GSIS) in INS-1 832/13 β-cells. Here, we demonstrate that glucose concentration directly regulates β-cell Nr4a1 expression. We show that 11 mM glucose increases Nr4a1 expression in INS-1 832/13 β-cells and primary mouse islets. We show that glucose functions through the cAMP/PKA/CREB pathway to regulate Nr4a1 mRNA and protein expression. Using Nr4a1-/- animals, we show that Nr4a1 is necessary for GSIS and systemic glucose handling. Using RNA-seq, we define Nr4a1-regulated pathways in response to glucose in the mouse islet, including Glut2 expression. Our data suggest that Nr4a1 plays a critical role in the β-cells response to the fed state.NEW & NOTEWORTHY Nr4a1 has a key role in fuel metabolism and β-cell function, but its exact role is unclear. Nr4a1 expression is regulated by glucose concentration using cAMP/PKA/CREB pathway. Nr4a1 regulates Glut2, Ndufa4, Ins1, In2, Sdhb, and Idh3g expression in response to glucose treatment. These results suggest that Nr4a1 is necessary for proper insulin secretion both through glucose uptake and metabolism machinery.

Diabetes mellitus type 2 (T2D) is associated with accelerated biological aging and the increased risk of onset of other age-related diseases. Epigenetic changes in DNA methylation levels have been found to serve as reliable biomarkers for biological aging. This study explores the relationship between various epigenetic biomarkers of aging and diabetes risk using longitudinal data. Data from the Swedish Adoption/Twin Study of Aging (SATSA) was collected from 1984 to 2014 and included 536 individuals with at least one epigenetic measurement. The following epigenetic biomarkers of aging were employed: DNAm PAI-1, DNAmTL, DunedinPACE, PCHorvath1, PCHorvath2, PCHannum, PCPhenoAge, and PCGrimAge. Firstly, longitudinal analysis of biomarker trajectories was done. Secondly, linear correlations between the biomarkers and time to diabetes were studied within individuals developing diabetes. Thirdly, Cox proportional hazards (PH) models were used to assess the associations between these biomarkers and time of diabetes diagnosis, with adjustments for chronological age, sex, education, smoking, blood glucose, and BMI. The longitudinal trajectories of the biomarkers revealed differences between individuals with and without diabetes. Smoothened average curves for DunedinPACE and DNAm PAI-1 were higher for individuals with diabetes around the age 60-70, compared to controls. Likewise, DunedinPACE and DNAm PAI-1 were higher closer to diabetes onset. However, no significant associations were found between the epigenetic biomarkers of aging and risk of diabetes in Cox PH models. Our findings suggest the potential value of developing epigenetic biomarkers specifically tailored to T2D, should we wish to model and explore the potential for predicting the disease.

Type 2 diabetes (T2D) is the fastest growing non-infectious disease worldwide. Impaired insulin secretion from pancreatic beta-cells is a hallmark of T2D, but the mechanisms behind this defect are insufficiently characterized. Integrating multiple layers of biomedical information, such as different Omics, may allow more accurate understanding of complex diseases such as T2D. Our aim was to explore and use Machine Learning to integrate multiple sources of biological/molecular information (multiOmics), in our case RNA-sequening, DNA methylation, SNP and phenotypic data from islet donors with T2D and non-diabetic controls. We exploited Machine Learning to perform multiOmics integration of DNA methylation, expression, SNPs, and phenotypes from pancreatic islets of 110 individuals, with ~ 30% being T2D cases. DNA methylation was analyzed using Infinium MethylationEPIC array, expression was analyzed using RNA-sequencing, and SNPs were analyzed using HumanOmniExpress arrays. Supervised linear multiOmics integration via DIABLO based on Partial Least Squares (PLS) achieved an accuracy of 91 ± 15% of T2D prediction with an area under the curve of 0.96 ± 0.08 on the test dataset after cross-validation. Biomarkers identified by this multiOmics integration, including SACS and TXNIP DNA methylation, OPRD1 and RHOT1 expression and a SNP annotated to ANO1, provide novel insights into the interplay between different biological mechanisms contributing to T2D. This Machine Learning approach of multiOmics cross-sectional data from human pancreatic islets achieved a promising accuracy of T2D prediction, which may potentially find broad applications in clinical diagnostics. In addition, it delivered novel candidate biomarkers for T2D and links between them across the different Omics.

DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid early detection and/or therapeutic treatment options for diabetics.

A systematic literature search for associations between T2DM and DNA methylation was performed. Prospero registration ID: CRD42020140436.

PubMed and ScienceDirect databases were searched (till October 19, 2023). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and New Castle Ottawa scale were used for reporting the selection and quality of the studies, respectively.

Thirty-two articles were selected. Four of 130 differentially methylated genes in blood, adipose, liver or pancreatic islets (TXNIP, ABCG1, PPARGC1A, PTPRN2) were reported in > 1 study. TXNIP was hypomethylated in diabetic blood across ethnicities. Gene enrichment analysis of the differentially methylated genes highlighted relevant disease pathways (T2DM, type 1 diabetes and adipocytokine signaling). Three prospective studies reported association of methylation in IGFBP2, MSI2, FTO, TXNIP, SREBF1, PHOSPHO1, SOCS3 and ABCG1 in blood at baseline with incident T2DM/hyperglycemia. Sex-specific differential methylation was reported only for HOOK2 in visceral adipose tissue (female diabetics: hypermethylated, male diabetics: hypomethylated). Gene expression was inversely associated with methylation status in 8 studies, in genes including ABCG1 (blood), S100A4 (adipose tissue), PER2 (pancreatic islets), PDGFA (liver) and PPARGC1A (skeletal muscle).

This review summarizes available evidence for using DNA methylation patterns to unravel T2DM pathophysiology. Further validation studies in diverse populations will set the stage for utilizing this knowledge for identifying early diagnostic markers and novel druggable pathways.

Alzheimer's disease (AD) is a neurodegenerative condition that predominantly affects the hippocampus and the entorhinal complex, leading to memory lapse and cognitive impairment. This can have a negative impact on an individual's behavior, speech, and ability to navigate their surroundings. AD is one of the principal causes of dementia. One of the most accepted theories in AD, the amyloid β (Aβ) hypothesis, assumes that the buildup of the peptide Aβ is the root cause of AD. Impaired insulin signaling in the periphery and central nervous system has been considered to have an effect on the pathophysiology of AD. Further, researchers have shifted their focus to epigenetic mechanisms that are responsible for dysregulating major biochemical pathways and intracellular signaling processes responsible for directly or indirectly causing AD. The prime epigenetic mechanisms encompass DNA methylation, histone modifications, and non-coding RNA, and are majorly responsible for impairing insulin signaling both centrally and peripherally, thus leading to AD. In this review, we provide insights into the major epigenetic mechanisms involved in causing AD, such as DNA methylation and histone deacetylation. We decipher how the mechanisms alter peripheral insulin signaling and brain insulin signaling, leading to AD pathophysiology. In addition, this review also discusses the need for newer drug delivery systems for the targeted delivery of epigenetic drugs and explores targeted drug delivery systems such as nanoparticles, vesicular systems, networks, and other nano formulations in AD. Further, this review also sheds light on the future approaches used for epigenetic drug delivery.

Metabolic diseases and their complications impose health and economic burdens worldwide. Evidence from past experimental studies and clinical trials suggests our body may have the ability to remember the past metabolic environment, such as hyperglycemia or hyperlipidemia, thus leading to chronic inflammatory disorders and other diseases even after the elimination of these metabolic environments. The long-term effects of that aberrant metabolism on the body have been summarized as metabolic memory and are found to assume a crucial role in states of health and disease. Multiple molecular mechanisms collectively participate in metabolic memory management, resulting in different cellular alterations as well as tissue and organ dysfunctions, culminating in disease progression and even affecting offspring. The elucidation and expansion of the concept of metabolic memory provides more comprehensive insight into pathogenic mechanisms underlying metabolic diseases and complications and promises to be a new target in disease detection and management. Here, we retrace the history of relevant research on metabolic memory and summarize its salient characteristics. We provide a detailed discussion of the mechanisms by which metabolic memory may be involved in disease development at molecular, cellular, and organ levels, with emphasis on the impact of epigenetic modulations. Finally, we present some of the pivotal findings arguing in favor of targeting metabolic memory to develop therapeutic strategies for metabolic diseases and provide the latest reflections on the consequences of metabolic memory as well as their implications for human health and diseases.

The field of epigenetics broadly seeks to define heritable phenotypic modifications that occur within cells without changes to the underlying DNA sequence. These modifications allow for precise control and specificity of function between cell types-ultimately creating complex organ systems that all contain the same DNA but only have access to the genes and sequences necessary for their cell-type-specific functions. The pancreas is an organ that contains varied cellular compartments with functions ranging from highly regulated glucose-stimulated insulin secretion in the β-cell to the pancreatic ductal cells that form a tight epithelial lining for the delivery of digestive enzymes. With diabetes cases on the rise worldwide, understanding the epigenetic mechanisms driving β-cell identity, function, and even disease is particularly valuable. In this chapter, we will discuss the known epigenetic modifications in pancreatic islet cells, how they are deposited, and the environmental and metabolic contributions to epigenetic mechanisms. We will also explore how a deeper understanding of epigenetic effectors can be used as a tool for diabetes therapeutic strategies.

Diabetes mellitus (DM) has become a significant health concern with an increasing rate of morbidity and mortality worldwide. India ranks second in the number of diabetes cases in the world. The increasing burden of DM can be explained by genetic predisposition of Indians to type 2 diabetes mellitus (T2DM) coupled with rapid urbanization and socio-economic development in the last 3 decades leading to drastic changes in lifestyle. Environment and lifestyle changes contribute to T2DM development by altering epigenetic processes such as DNA methylation, histone post-translational modifications, and long non-coding RNAs, all of which regulate chromatin structure and gene expression. Although the genetic predisposition of Indians to T2DM is well established, how environmental and genetic factors interact and lead to T2DM is not well understood. In this review, we discuss the prevalence of diabetes and its complications across different states in India and how various risk factors contribute to its pathogenesis. The review also highlights the role of genetic predisposition among the Indian population and epigenetic factors involved in the etiology of diabetes. Lastly, we review current treatments and emphasize the knowledge gap with respect to genetic and epigenetic factors in the Indian context. Further understanding of the genetic and epigenetic determinants will help in risk prediction and prevention as well as therapeutic interventions, which will improve the clinical management of diabetes and associated macro- and micro-vascular complications.

Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.

The inhibition of mammalian target of rapamycin (mTOR) with rapamycin (RAPA) provides protection against myocardial ischemia/reperfusion (I/R) injury in diabetes. Since interactions between transcripts, including long non-coding RNA (lncRNA), microRNA(miRNA) and mRNA, regulate the pathophysiology of disease, we performed unbiased miRarray profiling in the heart of diabetic rabbits following I/R injury with/without RAPA treatment to identify differentially expressed (DE) miRNAs and their predicted targets of lncRNAs/mRNAs. Results showed that among the total of 806 unique miRNAs targets, 194 miRNAs were DE after I/R in diabetic rabbits. Specifically, eight miRNAs, including miR-199a-5p, miR-154-5p, miR-543-3p, miR-379-3p, miR-379-5p, miR-299-5p, miR-140-3p, and miR-497-5p, were upregulated and 10 miRNAs, including miR-1-3p, miR-1b, miR-29b-3p, miR-29c-3p, miR-30e-3p, miR-133c, miR-196c-3p, miR-322-5p, miR-499-5p, and miR-672-5p, were significantly downregulated after I/R injury. Interestingly, RAPA treatment significantly reversed these changes in miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated the participation of miRNAs in the regulation of several signaling pathways related to I/R injury, including MAPK signaling and apoptosis. Furthermore, in diabetic hearts, the expression of lncRNAs, HOTAIR, and GAS5 were induced after I/R injury, but RAPA suppressed these lncRNAs. In contrast, MALAT1 was significantly reduced following I/R injury, with the increased expression of miR-199a-5p and suppression of its target, the anti-apoptotic protein Bcl-2. RAPA recovered MALAT1 expression with its sponging effect on miR-199-5p and restoration of Bcl-2 expression. The identification of novel targets from the transcriptome analysis in RAPA-treated diabetic hearts could potentially lead to the development of new therapeutic strategies for diabetic patients with myocardial infarction.

Background: Dulaglutide emerged as a promising therapeutic option for diabetes mellitus Type 2 (DM2). Aims: Owing to epigenetic similarities between the pathophysiology of DM2 and breast cancer (BC), we investigated the antitumor effect of dulaglutide. Materials & methods: To investigate the effect of dulaglutide, we analyzed the expression of methylated gene promoter regions in BC (ESR1, CDH1 and ADAM33). Results: Dulaglutide increased the expression of ESR1, CDH1 and ADAM33 up to fourfold in the MDA-MB-231 lineage by demethylating the gene promoter regions. This effect was translated to in vivo antitumoral activity and revealed significant tumor inhibition by combining the half-dose of methotrexate with dulaglutide. Conclusion: This therapy may mitigate the severe side effects commonly associated with chemotherapy.

Given that exosome nanovesicles constitute various growth factors, miRNAs and lncRNAs, they have implications for epigenetic modifications. Few studies have shown that exosomes from mesenchymal stem cells (MSCs) exhibit therapeutic effects on diabetic complications by substituting miRNAs and regulating histone modifications. Therefore, reversing epigenetic aberrations in diabetes may provide new insight into its treatment. This review discusses the impact of DNA and histone methylations on the development of diabetes and its complications. Further, we talk about miRNAs dysregulated in diabetic conditions and the possibility of utilizing mesenchymal stem cell (MSC) exosomes for the development of miRNA cell-free therapy and epigenetic modifiers in reversing diabetic-induced epigenetic alterations.

Type 2 diabetes (T2D) is a metabolic disease characterized by the development of β-cell dysfunction with hepatic, muscular and adipose tissue insulin resistance. Although the molecular mechanisms leading to its development are not entirely known, investigations of its causes reveal a multifactorial contribution to its development and progression in most cases. In addition, regulatory interactions mediated by epigenetic modifications such as DNA methylation, histone tail modifications and regulatory RNAs have been found to play a significant role in the etiology of T2D. In this chapter, we discuss the role of DNA methylation and its dynamics in the development of the pathological features of T2D.

Type 2 diabetes (T2D) is caused by insufficient insulin secretion from pancreatic β cells. To identify candidate genes contributing to T2D pathophysiology, we studied human pancreatic islets from approximately 300 individuals. We found 395 differentially expressed genes (DEGs) in islets from individuals with T2D, including, to our knowledge, novel (OPRD1, PAX5, TET1) and previously identified (CHL1, GLRA1, IAPP) candidates. A third of the identified expression changes in islets may predispose to diabetes, as expression of these genes associated with HbA1c in individuals not previously diagnosed with T2D. Most DEGs were expressed in human β cells, based on single-cell RNA-Seq data. Additionally, DEGs displayed alterations in open chromatin and associated with T2D SNPs. Mouse KO strains demonstrated that the identified T2D-associated candidate genes regulate glucose homeostasis and body composition in vivo. Functional validation showed that mimicking T2D-associated changes for OPRD1, PAX5, and SLC2A2 impaired insulin secretion. Impairments in Pax5-overexpressing β cells were due to severe mitochondrial dysfunction. Finally, we discovered PAX5 as a potential transcriptional regulator of many T2D-associated DEGs in human islets. Overall, we have identified molecular alterations in human pancreatic islets that contribute to β cell dysfunction in T2D pathophysiology.

In recent years, there has been a significant increase in age-related diseases due to the improvement in life expectancy worldwide. The pancreas undergoes various morphological and pathological changes with aging, such as pancreatic atrophy, fatty degeneration, fibrosis, inflammatory cell infiltration, and exocrine pancreatic metaplasia. Meanwhile, these may predispose the individuals to aging-related diseases, such as diabetes, dyspepsia, pancreatic ductal adenocarcinoma, and pancreatitis, as the endocrine and exocrine functions of the pancreas are significantly affected by aging. Pancreatic senescence is associated with various underlying factors including genetic damage, DNA methylation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and inflammation. This paper reviews the alternations of morphologies and functions in the aging pancreas, especially β-cells, closely related to insulin secretion. Finally, we summarize the mechanisms of pancreatic senescence to provide potential targets for treating pancreatic aging-related diseases.

A long-term complication of obesity is the development of type 2 diabetes (T2D). Patients with T2D have been described as having epigenetic modifications. Epigenetics is the post-transcriptional modification of DNA or associated factors containing genetic information. These environmentally-influenced modifications, maintained during cell division, cause stable changes in gene expression. Epigenetic modifications of T2D are DNA methylation, acetylation, ubiquitylation, SUMOylation, and phosphorylation at the lysine residue at the amino terminus of histones, affecting DNA, histones, and non-coding RNA. DNA methylation has been shown in pancreatic islets, adipose tissue, skeletal muscle, and the liver. Furthermore, epigenetic changes have been observed in chronic complications of T2D, such as diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. Recently, a new drug has been developed which acts on bromodomains and extraterminal (BET) domain proteins, which operate like epigenetic readers and communicate with chromatin to make DNA accessible for transcription by inhibiting them. This drug (apabetalone) is being studied to prevent major adverse cardiovascular events in people with T2D, low HDL cholesterol, chronic kidney failure, and recent coronary events. This review aims to describe the relationship between obesity, long-term complications such as T2D, and epigenetic modifications and their possible treatments.

Diabetes has been a worldwide healthcare problem for many years. Current methods of treating diabetes are still largely directed at symptoms, aiming to control the manifestations of the pathology. This creates an overall need to find alternative measures that can impact on the causes of the disease, reverse diabetes, or make it more manageable. Understanding the role of key players in the pathogenesis of diabetes and the related β-cell functions is of great importance in combating diabetes. PDX1 is a master regulator in pancreas organogenesis, the maturation and identity preservation of β-cells, and of their role in normal insulin function. Mutations in the PDX1 gene are correlated with many pancreatic dysfunctions, including pancreatic agenesis (homozygous mutation) and MODY4 (heterozygous mutation), while in other types of diabetes, PDX1 expression is reduced. Therefore, alternative approaches to treat diabetes largely depend on knowledge of PDX1 regulation, its interaction with other transcription factors, and its role in obtaining β-cells through differentiation and transdifferentiation protocols. In this article, we review the basic functions of PDX1 and its regulation by genetic and epigenetic factors. Lastly, we summarize different variations of the differentiation protocols used to obtain β-cells from alternative cell sources, using PDX1 alone or in combination with various transcription factors and modified culture conditions. This review shows the unique position of PDX1 as a potential target in the genetic and cellular treatment of diabetes.

In this perspective, we provide an overview of a recently established National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) initiative, the Human Pancreas Analysis Program for Type 2 Diabetes (HPAP-T2D). This program is designed to define the molecular pathogenesis of islet dysfunction by studying human pancreatic tissue samples from organ donors with T2D. HPAP-T2D generates detailed datasets of physiological, histological, transcriptomic, epigenomic, and genomic information. Importantly, all data collected, generated, and analyzed by HPAP-T2D are made immediately and freely available through a centralized database, PANC-DB, thus providing a comprehensive data resource for the diabetes research community.

Data generated over nearly two decades clearly demonstrate the importance of epigenetic modifications and mechanisms in the pathogenesis of type 2 diabetes. However, the role of pharmacoepigenetics in type 2 diabetes is less well established. The field of pharmacoepigenetics covers epigenetic biomarkers that predict response to therapy, therapy-induced epigenetic alterations as well as epigenetic therapies including inhibitors of epigenetic enzymes. Not all individuals with type 2 diabetes respond to glucose-lowering therapies in the same way, and there is therefore a need for clinically useful biomarkers that discriminate responders from non-responders. Blood-based epigenetic biomarkers may be useful for this purpose. There is also a need for a better understanding of whether existing glucose-lowering therapies exert their function partly through therapy-induced epigenetic alterations. Finally, epigenetic enzymes may be drug targets for type 2 diabetes. Here, I discuss whether pharmacoepigenetics is clinically relevant for type 2 diabetes based on studies addressing this topic.

Type 2 diabetes (T2D) was recently reclassified into severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications.

Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications.

We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6-6.1 per 1-SD increase, P < 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4-1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue.

We identified differential epigenetic patterns between T2D subgroups that associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.

Pioneering studies performed over the past few decades demonstrate links between epigenetics and type 2 diabetes mellitus (T2DM), the metabolic disorder with the most rapidly increasing prevalence in the world. Importantly, these studies identified epigenetic modifications, including altered DNA methylation, in pancreatic islets, adipose tissue, skeletal muscle and the liver from individuals with T2DM. As non-genetic factors that affect the risk of T2DM, such as obesity, unhealthy diet, physical inactivity, ageing and the intrauterine environment, have been associated with epigenetic modifications in healthy individuals, epigenetics probably also contributes to T2DM development. In addition, genetic factors associated with T2DM and obesity affect the epigenome in human tissues. Notably, causal mediation analyses found DNA methylation to be a potential mediator of genetic associations with metabolic traits and disease. In the past few years, translational studies have identified blood-based epigenetic markers that might be further developed and used for precision medicine to help patients with T2DM receive optimal therapy and to identify patients at risk of complications. This Review focuses on epigenetic mechanisms in the development of T2DM and the regulation of body weight in humans, with a special focus on precision medicine.

With the presentation of the blueprint of the first human genome in 2001 and the advent of technologies for high-throughput genetic analysis, personalized nutrition (PN) became a new scientific field and the first commercial offerings of genotype-based nutrition advice emerged at the same time. Here, we summarize the state of evidence for the effect of genetic and epigenetic factors in the development of obesity, the metabolic syndrome and resulting illnesses such as non-insulin-dependent diabetes mellitus and cardiovascular diseases. We also critically value the concepts of PN that were built around the new genetic avenue from both the academic and a commercial perspective and their effectiveness in causing sustained changes in diet, lifestyle and for improving health. Despite almost 20 years of research and commercial direct-to-consumer offerings, evidence for the success of gene-based dietary recommendations is still generally lacking. This calls for new concepts of future PN solutions that incorporate more phenotypic measures and provide a panel of instruments (e.g., self- and bio-monitoring tools, feedback systems, algorithms based on artificial intelligence) that increases compliance based on the individual´s physical and social environment and value system. This article is protected by copyright. All rights reserved.

Obesity is a major risk factor for atherosclerotic cardiovascular disease (ASCVD) and is associated with altered platelet function. The mean platelet volume (MPV) is a rapid measure of platelet activation and a prognostic marker in patients with cardiovascular disease. However, no meta-analysis on the association between MPV and obesity has been conducted, and the value of monitoring the MPV in patients with obesity remains unclear.

To provide cumulative evidence on whether the mean platelet volume (MPV) is increased in individuals with obesity and to describe associations between the ASCVD-risk factors and the MPV in individuals with obesity.

This meta-analysis was prepared following the Meta-analysis Of Observational Studies (MOOSE) guidelines. We searched the PubMed and Embase database from inception until the 31st of March 2021. Studies were included when they reported the mean platelet volume in individuals with obesity and provided a suitable non-obese comparator group. The risk of bias was independently assessed by two reviewers using the Newcastle-Ottawa scale. The primary outcome of the meta-analysis was the MPV, while we considered the atherosclerotic risk profiles as a secondary outcome.

We identified 178 citations through the PUBMED and 255 citations through EMBASE database search. In all, 13 studies met the inclusion criteria. Firstly, we report an increased mean platelet volume in individuals with obesity compared to non-obese individuals (MD 0.79; [95%CI: 0.42 to 1.16], I2 = 93.4%). Moreover, the reported increase in the MPV was inversely associated with the body mass index (Coefficient: -0.57, standard error (SE): 0.18, p < 0.001) and directly related to changes in triglyceride levels (Coefficient: 4.99, standard error (SE): 1.14, p < 0.001).

This meta-analysis and meta-regression showed an increased MPV in nondiabetic individuals living with obesity. Moreover, the MPV was associated with hypertriglyceridemia, an independent predictor of atherosclerotic cardiovascular disease. Overall, the findings suggest that MPV may be a valuable rapid marker for the monitoring and risk-stratification of individuals with obesity who may be at risk of developing cardiovascular disease.

Modern lifestyle, genetics, nutritional overload through high-fat diet attributed prevalence and diabetes outcomes with various complications primarily due to obesity in which energy-dense diets frequently affect metabolic health. One possible issue usually associated with elevated chronic fat intake is insulin resistance, and hyperglycaemia constitutes an important function in altering the carbohydrates and lipids metabolism. Similarly, in assessing human susceptibility to weight gain and obesity, genetic variations play a central role, contributing to keen interest in identifying the possible role of epigenetics as a mediator of gene-environmental interactions influencing the production of type 2 diabetes mellitus and its related concerns. Epigenetic modifications associated with the acceptance of a sedentary lifestyle and environmental stress factors in response to energy intake and expenditure imbalances complement genetic alterations and lead to the production and advancement of metabolic disorders such as diabetes and obesity. Methylation of DNA, histone modifications and increases in the expression of non-coding RNAs can result in reduced transcriptional activity of key β-cell genes thus creating insulin resistance. Epigenetics contribute to changes in the expression of the underlying insulin resistance and insufficiency gene networks, along with low-grade obesity-related inflammation, increased ROS generation and DNA damage in multi organs. This review focused on epigenetic mechanisms and metabolic regulations associated with high fat diet (HFD)-induced diabetes mellitus.

Over time, the human DNA methylation landscape accrues substantial damage, which has been associated with a broad range of age-related diseases, including cardiovascular disease and cancer. Various age-related DNA methylation changes have been described, including at the level of individual CpGs, such as differential and variable methylation, and at the level of the whole methylome, including entropy and correlation networks. Here, we review these changes in the ageing methylome as well as the statistical tools that can be used to quantify them. We detail the evidence linking DNA methylation to ageing phenotypes and the longevity strategies aimed at altering both DNA methylation patterns and machinery to extend healthspan and lifespan. Lastly, we discuss theories on the mechanistic causes of epigenetic ageing.

The ability to detect and target β cells in vivo can substantially refine how diabetes is studied and treated. However, the lack of specific probes still hampers a precise characterization of human β cell mass and the delivery of therapeutics in clinical settings. Here, we report the identification of two RNA aptamers that specifically and selectively recognize mouse and human β cells. The putative targets of the two aptamers are transmembrane p24 trafficking protein 6 (TMED6) and clusterin (CLUS). When given systemically in immune deficient mice, these aptamers recognize the human islet graft producing a fluorescent signal proportional to the number of human islets transplanted. These aptamers cross-react with endogenous mouse β cells and allow monitoring the rejection of mouse islet allografts. Finally, once conjugated to saRNA specific for X-linked inhibitor of apoptosis (XIAP), they can efficiently transfect non-dissociated human islets, prevent early graft loss, and improve the efficacy of human islet transplantation in immunodeficient in mice.

The American Heart Association, in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).

The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2022 Statistical Update is the product of a full year's worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year's edition includes data on the monitoring and benefits of cardiovascular health in the population and an enhanced focus on social determinants of health, adverse pregnancy outcomes, vascular contributions to brain health, and the global burden of cardiovascular disease and healthy life expectancy.

Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.

The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Intrauterine growth restriction (IUGR) leads to the development of type 2 diabetes in adulthood, and the permanent alterations in gene expression implicate an epigenetic mechanism. Using a rat model of IUGR, we performed TrueSeq-HELP Tagging to assess the association of DNA methylation changes and gene dysregulation in islets. We identified 511 differentially methylated regions (DMRs) and 4377 significantly altered single CpG sites. Integrating the methylome and our published transcriptome data sets resulted in the identification of pathways critical for islet function. The identified DMRs were enriched with transcription factor binding motifs, such as Elk1, Etv1, Foxa1, Foxa2, Pax7, Stat3, Hnf1, and AR. In silico analysis of 3-dimensional chromosomal interactions using human pancreas and islet Hi-C data sets identified interactions between 14 highly conserved DMRs and 35 genes with significant expression changes at an early age, many of which persisted in adult islets. In adult islets, there were far more interactions between DMRs and genes with significant expression changes identified with Hi-C, and most of them were critical to islet metabolism and insulin secretion. The methylome was integrated with our published genome-wide histone modification data sets from IUGR islets, resulting in further characterization of important regulatory regions of the genome altered by IUGR containing both significant changes in DNA methylation and specific histone marks. We identified novel regulatory regions in islets after exposure to IUGR, suggesting that epigenetic changes at key transcription factor binding motifs and other gene regulatory regions may contribute to gene dysregulation and an abnormal islet phenotype in IUGR rats.

A recent International Diabetes Federation report suggests that more than 463 million people between 20 and 79 years have diabetes. Of the 20 million women affected by hyperglycemia during pregnancy, 84% have gestational diabetes. In addition, more than 1.1 million children or adolescents are affected by type 1 diabetes. Factors contributing to the increase in diabetes prevalence are complex and include contributions from genetic, environmental, and epigenetic factors. However, molecular regulatory mechanisms influencing the progression of an individual towards increased susceptibility to metabolic diseases such as diabetes are not fully understood. Recent studies suggest that the pathogenesis of diabetes involves epigenetic changes, resulting in a persistently dysregulated metabolic phenotype. This review summarizes the role of epigenetic mechanisms, mainly DNA methylation and histone modifications, in the development of the pancreas, their contribution to the development of diabetes, and the potential employment of epigenetic modulators in diabetes treatment.

Pancreatic β cell dysfunction is a central component of diabetes progression. During the last decades, the genetic basis of several monogenic forms of diabetes has been recognized. Genome-wide association studies (GWAS) have also facilitated the identification of common genetic variants associated with an increased risk of diabetes. These studies highlight the importance of impaired β cell function in all forms of diabetes. However, how most of these risk variants confer disease risk, remains unanswered. Understanding the specific contribution of genetic variants and the precise role of their molecular effectors is the next step toward developing treatments that target β cell dysfunction in the era of personalized medicine. Protocols that allow derivation of β cells from pluripotent stem cells, represent a powerful research tool that allows modeling of human development and versatile experimental designs that can be used to shed some light on diabetes pathophysiology. This article reviews different models to study the genetic basis of β cell dysfunction, focusing on the recent advances made possible by stem cell applications in the field of diabetes research.