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Changes in DNA Methylation and Gene Expression of Insulin and Obesity-Related Gene PIK3R1 after Roux-en-Y Gastric Bypass

by Marcela A S Pinhel, Natália Y Noronha, Carolina F Nicoletti, Vanessa AB Pereira, Bruno AP de Oliveira, Cristiana Cortes-Oliveira, Wilson Salgado, Jr., Fernando Barbosa, Jr., Júlio S Marchini, Doroteia RS Souza and Carla B Nonino

Int. J. Mol. Sci. 2020, 21(12), 4476; https://doi.org/10.3390/ijms21124476 - 24 Jun 2020

Cited by 10 | Viewed by 2250

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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13 pages, 1453 KiB

Open AccessArticle

Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology

by Rebecca C. Rancourt, Raffael Ott, Thomas Ziska, Karen Schellong, Kerstin Melchior, Wolfgang Henrich and Andreas Plagemann

Int. J. Mol. Sci. 2020, 21(2), 479; https://doi.org/10.3390/ijms21020479 - 12 Jan 2020

Cited by 22 | Viewed by 4119

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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17 pages, 1464 KiB

Open AccessArticle

Blood Co-Circulating Extracellular microRNAs and Immune Cell Subsets Associate with Type 1 Diabetes Severity

by Silvia Garavelli, Sara Bruzzaniti, Elena Tagliabue, Francesco Prattichizzo, Dario Di Silvestre, Francesco Perna, Lucia La Sala, Antonio Ceriello, Enza Mozzillo, Valentina Fattorusso, Pierluigi Mauri, Annibale A. Puca, Adriana Franzese, Giuseppe Matarese, Mario Galgani and Paola de Candia

Int. J. Mol. Sci. 2020, 21(2), 477; https://doi.org/10.3390/ijms21020477 - 11 Jan 2020

Cited by 25 | Viewed by 4134

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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13 pages, 820 KiB

Open AccessArticle

Mediation Analysis Supports a Causal Relationship between Maternal Hyperglycemia and Placental DNA Methylation Variations at the Leptin Gene Locus and Cord Blood Leptin Levels

by Valérie Gagné-Ouellet, Edith Breton, Kathrine Thibeault, Carol-Ann Fortin, Andres Cardenas, Renée Guérin, Patrice Perron, Marie-France Hivert and Luigi Bouchard

Int. J. Mol. Sci. 2020, 21(1), 329; https://doi.org/10.3390/ijms21010329 - 03 Jan 2020

Cited by 18 | Viewed by 3302

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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15 pages, 1731 KiB

Open AccessArticle

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

by Ana Arpón, José L. Santos, Fermín I. Milagro, Luis Rodrigo Cataldo, Carolina Bravo, José-Ignacio Riezu-Boj and J. Alfredo Martínez

Int. J. Mol. Sci. 2019, 20(12), 2928; https://doi.org/10.3390/ijms20122928 - 15 Jun 2019

Cited by 6 | Viewed by 3573

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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18 pages, 2037 KiB

Open AccessReview

Epigenetic Regulation of Circadian Rhythm and Its Possible Role in Diabetes Mellitus

by Michael Hudec, Pavlina Dankova, Roman Solc, Nardjas Bettazova and Marie Cerna

Int. J. Mol. Sci. 2020, 21(8), 3005; https://doi.org/10.3390/ijms21083005 - 24 Apr 2020

Cited by 17 | Viewed by 6068

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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13 pages, 429 KiB

Open AccessReview

Genes and Diet in the Prevention of Chronic Diseases in Future Generations

by Marica Franzago, Daniele Santurbano, Ester Vitacolonna and Liborio Stuppia

Int. J. Mol. Sci. 2020, 21(7), 2633; https://doi.org/10.3390/ijms21072633 - 10 Apr 2020

Cited by 61 | Viewed by 14426

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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17 pages, 1709 KiB

Open AccessReview

Epigenetic Regulation in Etiology of Type 1 Diabetes Mellitus

by Marie Cerna

Int. J. Mol. Sci. 2020, 21(1), 36; https://doi.org/10.3390/ijms21010036 - 19 Dec 2019

Cited by 39 | Viewed by 7498

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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