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Special Issue "Epigenetics of Diabetes and Related Complications"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 November 2019).

Special Issue Editors

Dr. Claudia Miele
E-Mail Website
Guest Editor
URT Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore” CNR, Naples, Italy
Interests: signal transduction; glucose metabolism; type 2 diabetes; insulin resistance; beta-cell function; glucotoxicity; epigenetic of type 2 diabetes; diabetes and cognitive diseases; diabetes and cancer
Special Issues and Collections in MDPI journals
Prof. Francesco Beguinot
E-Mail Website
Guest Editor
National Council of Research, URT of the Institute of Experimental Endocrinology and Oncology “G. Salvatore”, Naples, Italy
Interests: type 2 Diabetes; diabetes epigenetics; genetic of T2D; insulin action and signalling; insulin resistance; insulin secretion

Special Issue Information

Dear colleagues,

A growing body of evidence suggests that dynamic alterations in the epigenome (i.e., DNA methylation, histone marks, and non-coding RNAs) play a causative role in the activation of the molecular events responsible for diabetes progression and associated complications. These events can be induced by metabolic changes, such as hyperglycaemia, and can be responsible for a long-lasting impairment of vascular and cardiac function, even after intensive glycemic control. Indeed, diabetes complications can be affected by glucose levels that were experienced years earlier, a phenomenon called metabolic memory. Notably, the adverse epigenetic profile acquired over the life course can be transmitted to the offspring, and may contribute to early cardiovascular phenotypes in younger generations.

Unveiling the epigenetic landscape in diabetic subjects and people at risk of developing diabetes is beneficial to provide tools for personalized epigenetic-based therapies.

The aim of this Special Issue is to provide a collection of original and review articles aimed at advancing the current knowledge of the epigenetics of diabetes and its implications in classic diabetes complications and co-morbidities.

Assoc. Dr. Claudia Miele
Prof. Francesco Beguinot
Guest Editors

Manuscript Submission Information

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Keywords

  • Diabetes mellitus
  • Epigenetics
  • Glycation stress
  • Histone marks
  • Metabolic memory
  • Methylation
  • ncRNA
  • Vascular complications
  • Cognitive disease
  • Cancer risk

Published Papers (8 papers)

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Research

Jump to: Review

Communication
Changes in DNA Methylation and Gene Expression of Insulin and Obesity-Related Gene PIK3R1 after Roux-en-Y Gastric Bypass
Int. J. Mol. Sci. 2020, 21(12), 4476; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21124476 - 24 Jun 2020
Viewed by 662
Abstract
Weight regulation and the magnitude of weight loss after a Roux-en-Y gastric bypass (RYGB) can be genetically determined. DNA methylation patterns and the expression of some genes can be altered after weight loss interventions, including RYGB. The present study aimed to evaluate how [...] Read more.
Weight regulation and the magnitude of weight loss after a Roux-en-Y gastric bypass (RYGB) can be genetically determined. DNA methylation patterns and the expression of some genes can be altered after weight loss interventions, including RYGB. The present study aimed to evaluate how the gene expression and DNA methylation of PIK3R1, an obesity and insulin-related gene, change after RYGB. Blood samples were obtained from 13 women (35.9 ± 9.2 years) with severe obesity before and six months after surgical procedure. Whole blood transcriptome and epigenomic patterns were assessed by microarray-based, genome-wide technologies. A total of 1966 differentially expressed genes were identified in the pre- and postoperative periods of RYGB. From these, we observed that genes involved in obesity and insulin pathways were upregulated after surgery. Then, the PIK3R1 gene was selected for further RT-qPCR analysis and cytosine-guanine nucleotide (CpG) sites methylation evaluation. We observed that the PI3KR1 gene was upregulated, and six DNA methylation CpG sites were differently methylated after bariatric surgery. In conclusion, we found that RYGB upregulates genes involved in obesity and insulin pathways. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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Article
Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology
Int. J. Mol. Sci. 2020, 21(2), 479; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020479 - 12 Jan 2020
Cited by 5 | Viewed by 1238
Abstract
Gestational diabetes (GDM) is among the most challenging diseases in westernized countries, affecting mother and child, immediately and in later life. Obesity is a major risk factor for GDM. However, the impact visceral obesity and related epigenetics play for GDM etiopathogenesis have hardly [...] Read more.
Gestational diabetes (GDM) is among the most challenging diseases in westernized countries, affecting mother and child, immediately and in later life. Obesity is a major risk factor for GDM. However, the impact visceral obesity and related epigenetics play for GDM etiopathogenesis have hardly been considered so far. Our recent findings within the prospective ‘EaCH’ cohort study of women with GDM or normal glucose tolerance (NGT), showed the role, critical factors of insulin resistance (i.e., adiponectin, insulin receptor) may have for GDM pathophysiology with epigenetically modified expression in subcutaneous (SAT) and visceral (VAT) adipose tissues. Here we investigated the expression and promoter methylation of key inflammatory candidates, tumor necrosis factor-alpha (TNF-α) and suppressor of cytokine signaling 3 (SOCS3) in maternal adipose tissues collected during caesarian section (GDM, n = 19; NGT, n = 22). The mRNA expression of TNF-α and SOCS3 was significantly increased in VAT, but not in SAT, of GDM patients vs. NGT, accompanied by specific alterations of respective promoter methylation patterns. In conclusion, we propose a critical role of VAT and visceral obesity for the pathogenesis of GDM, with epigenetic alterations of the expression of inflammatory factors as a potential factor. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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Article
Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity
Int. J. Mol. Sci. 2020, 21(2), 477; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020477 - 11 Jan 2020
Cited by 10 | Viewed by 1654
Abstract
Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children [...] Read more.
Immune cell subsets and microRNAs have been independently proposed as type 1 diabetes (T1D) diagnostic and/or prognostic biomarkers. Here, we aimed to analyze the relationships between peripheral blood circulating immune cell subsets, plasmatic microRNAs, and T1D. Blood samples were obtained from both children with T1D at diagnosis and age-sex matched healthy controls. Then, immunophenotype assessed by flow cytometry was coupled with the quantification of 60 plasmatic microRNAs by quantitative RT-PCR. The associations between immune cell frequency, plasmatic microRNAs, and the parameters of pancreatic loss, glycemic control, and diabetic ketoacidosis were assessed by logistic regression models and correlation analyses. We found that the increase in specific plasmatic microRNAs was associated with T1D disease onset (let-7c-5p, let-7d-5p, let-7f-5p, let-7i-5p, miR-146a-5p, miR-423-3p, and miR-423-5p), serum C-peptide concentration (miR-142-5p and miR-29c-3p), glycated hemoglobin (miR-26a-5p and miR-223-3p) and the presence of ketoacidosis (miR-29c-3p) more strongly than the evaluated immune cell subset frequency. Some of these plasmatic microRNAs were shown to positively correlate with numbers of blood circulating B lymphocytes (miR-142-5p) and CD4+CD45RO+ (miR-146a-5p and miR-223-3p) and CD4+CD25+ cells (miR-423-3p and miR-223-3p) in children with T1D but not in healthy controls, suggesting a disease-specific microRNA association with immune dysregulation in T1D. In conclusion, our results suggest that, while blood co-circulating extracellular microRNAs and immune cell subsets may be biologically linked, microRNAs may better provide powerful information about T1D onset and severity. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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Article
Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels
Int. J. Mol. Sci. 2020, 21(1), 329; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010329 - 03 Jan 2020
Cited by 2 | Viewed by 961
Abstract
Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5′-C-phosphate-G-3′ [...] Read more.
Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5′-C-phosphate-G-3′ (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother–child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (β = −2.69, p = 0.05) and fat distribution (β = −0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (β = −0.01, p = 0.04) and neonatal leptinemia (β = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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Article
Insulin Sensitivity Is Associated with Lipoprotein Lipase (LPL) and Catenin Delta 2 (CTNND2) DNA Methylation in Peripheral White Blood Cells in Non-Diabetic Young Women
Int. J. Mol. Sci. 2019, 20(12), 2928; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20122928 - 15 Jun 2019
Cited by 4 | Viewed by 1247
Abstract
Hyperglycaemia and type 2 diabetes (T2D) are associated with impaired insulin secretion and/or insulin action. Since few studies have addressed the relation between DNA methylation patterns with elaborated surrogates of insulin secretion/sensitivity based on the intravenous glucose tolerance test (IVGTT), the aim of [...] Read more.
Hyperglycaemia and type 2 diabetes (T2D) are associated with impaired insulin secretion and/or insulin action. Since few studies have addressed the relation between DNA methylation patterns with elaborated surrogates of insulin secretion/sensitivity based on the intravenous glucose tolerance test (IVGTT), the aim of this study was to evaluate the association between DNA methylation and an insulin sensitivity index based on IVGTT (calculated insulin sensitivity index (CSi)) in peripheral white blood cells from 57 non-diabetic female volunteers. The CSi and acute insulin response (AIR) indexes, as well as the disposition index (DI = CSi × AIR), were estimated from abbreviated IVGTT in 49 apparently healthy Chilean women. Methylation levels were assessed using the Illumina Infinium Human Methylation 450k BeadChip. After a statistical probe filtering, the two top CpGs whose methylation was associated with CSi were cg04615668 and cg07263235, located in the catenin delta 2 (CTNND2) and lipoprotein lipase (LPL) genes, respectively. Both CpGs conjointly predicted insulin sensitivity status with an area under the curve of 0.90. Additionally, cg04615668 correlated with homeostasis model assessment insulin-sensitivity (HOMA-S) and AIR, whereas cg07263235 was associated with plasma creatinine and DI. These results add further insights into the epigenetic regulation of insulin sensitivity and associated complications, pointing the CTNND2 and LPL genes as potential underlying epigenetic biomarkers for future risk of insulin-related diseases. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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Review

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Review
Epigenetic Regulation of Circadian Rhythm and Its Possible Role in Diabetes Mellitus
Int. J. Mol. Sci. 2020, 21(8), 3005; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21083005 - 24 Apr 2020
Cited by 4 | Viewed by 1411
Abstract
This review aims to summarize the knowledge about the relationship between circadian rhythms and their influence on the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Circadian rhythms are controlled by internal molecular feedback loops that synchronize the organism with the [...] Read more.
This review aims to summarize the knowledge about the relationship between circadian rhythms and their influence on the development of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Circadian rhythms are controlled by internal molecular feedback loops that synchronize the organism with the external environment. These loops are affected by genetic and epigenetic factors. Genetic factors include polymorphisms and mutations of circadian genes. The expression of circadian genes is regulated by epigenetic mechanisms that change from prenatal development to old age. Epigenetic modifications are influenced by the external environment. Most of these modifications are affected by our own life style. Irregular circadian rhythm and low quality of sleep have been shown to increase the risk of developing T2DM and other metabolic disorders. Here, we attempt to provide a wide description of mutual relationships between epigenetic regulation, circadian rhythm, aging process and highlight new evidences that show possible therapeutic advance in the field of chrono-medicine which will be more important in the upcoming years. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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Review
Genes and Diet in the Prevention of Chronic Diseases in Future Generations
Int. J. Mol. Sci. 2020, 21(7), 2633; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072633 - 10 Apr 2020
Cited by 8 | Viewed by 3153
Abstract
Nutrition is a modifiable key factor that is able to interact with both the genome and epigenome to influence human health and fertility. In particular, specific genetic variants can influence the response to dietary components and nutrient requirements, and conversely, the diet itself [...] Read more.
Nutrition is a modifiable key factor that is able to interact with both the genome and epigenome to influence human health and fertility. In particular, specific genetic variants can influence the response to dietary components and nutrient requirements, and conversely, the diet itself is able to modulate gene expression. In this context and the era of precision medicine, nutrigenetic and nutrigenomic studies offer significant opportunities to improve the prevention of metabolic disturbances, such as Type 2 diabetes, gestational diabetes, hypertension, and cardiovascular diseases, even with transgenerational effects. The present review takes into account the interactions between diet, genes and human health, and provides an overview of the role of nutrigenetics, nutrigenomics and epigenetics in the prevention of non-communicable diseases. Moreover, we focus our attention on the mechanism of intergenerational or transgenerational transmission of the susceptibility to metabolic disturbances, and underline that the reversibility of epigenetic modifications through dietary intervention could counteract perturbations induced by lifestyle and environmental factors. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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Review
Epigenetic Regulation in Etiology of Type 1 Diabetes Mellitus
Int. J. Mol. Sci. 2020, 21(1), 36; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010036 - 19 Dec 2019
Cited by 12 | Viewed by 1672
Abstract
Type 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of the pancreatic β-cells, a process in which autoreactive T cells play a pivotal role, and it is characterized by islet autoantibodies. Consequent hyperglycemia is requiring lifelong insulin replacement therapy. T1DM is [...] Read more.
Type 1 diabetes mellitus (T1DM) is caused by an autoimmune destruction of the pancreatic β-cells, a process in which autoreactive T cells play a pivotal role, and it is characterized by islet autoantibodies. Consequent hyperglycemia is requiring lifelong insulin replacement therapy. T1DM is caused by the interaction of multiple environmental and genetic factors. The integrations of environments and genes occur via epigenetic regulations of the genome, which allow adaptation of organism to changing life conditions by alternation of gene expression. T1DM has increased several-fold over the past half century. Such a short time indicates involvement of environment factors and excludes genetic changes. This review summarizes the most current knowledge of epigenetic changes in that process leading to autoimmune diabetes mellitus. Full article
(This article belongs to the Special Issue Epigenetics of Diabetes and Related Complications)
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