Genome-Wide DNA Methylation and LncRNA-Associated DNA Methylation in Metformin-Treated and -Untreated Diabetes

Solomon, Wendy; Hector, Stanton B.; Raghubeer, Shanel; Erasmus, Rajiv T; Kengne, André Pascal; Matsha, Tandi E.

doi:10.3390/epigenomes4030019

Cited by 7 publications

(4 citation statements)

References 39 publications

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“…Here we report, for the first time, a concordant negative association between two measurements reflecting carbohydrates’ quality and quantity (GI and GL), and global methylation levels measured within the same subjects from a general population. These associations resisted correction for several factors influencing hypomethylation, including use of metformin [ 24 , 25 ] or self-reported diabetic status.…”

Section: Discussionmentioning

confidence: 99%

Association of nutritional glycaemic indices with global DNA methylation patterns: results from the Moli-sani cohort

et al. 2022

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Background High dietary glycaemic index (GI) and load (GL) have been associated with increased risk of various cardiometabolic conditions. Among the molecular potential mechanisms underlying this relationship, DNA methylation has been studied, but a direct link between high GI and/or GL of diet and global DNA methylation levels has not been proved yet. We analyzed the associations between GI and GL and global DNA methylation patterns within an Italian population. Results Genomic DNA methylation (5mC) and hydroxymethylation (5hmC) levels were measured in 1080 buffy coat samples from participants of the Moli-sani study (mean(SD) = 54.9(11.5) years; 52% women) via ELISA. A 188-item Food Frequency Questionnaire was used to assess food intake and dietary GI and GL for each participant were calculated. Multiple linear regressions were used to investigate the associations between dietary GI and GL and global 5mC and 5hmC levels, as well as the proportion of effect explained by metabolic and inflammatory markers. We found negative associations of GI with both 5mC (β (SE) = − 0.073 (0.027), p = 0.007) and 5hmC (− 0.084 (0.030), p = 0.006), and of GL with 5mC (− 0.14 (0.060), p = 0.014). Circulating biomarkers did not explain the above-mentioned associations. Gender interaction analyses revealed a significant association of the gender-x-GL interaction with 5mC levels, with men showing an inverse association three times as negative as in women (interaction β (SE) = − 0.16 (0.06), p = 0.005). Conclusions Our findings suggest that global DNA methylation and hydroxymethylation patterns represent a biomarker of carbohydrate intake. Based on the differential association of GL with 5mC between men and women, further gender-based separate approaches are warranted.

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Section: Discussionmentioning

confidence: 99%

Association of nutritional glycaemic indices with global DNA methylation patterns: results from the Moli-sani cohort

et al. 2022

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“…Folic acid is an essential water-soluble vitamin for vertebrates. It is incorporated as an essential cofactor for nucleotide synthesis and the generation of S-adenosylmethionine (SAM), which functions as a methyl group donor for DNA, RNA, and proteins [55]. Maternal folate deficiency causes severe neural tube defects [56] and craniofacial abnormalities [57] in offspring.…”

Section: Prevention Of Transgenerational Transmission Of Disease Susc...mentioning

confidence: 99%

Prevention of transgenerational transmission of disease susceptibility through perinatal intervention

Nemoto,

Sagawa

2024

Endocr J

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The observational findings of Barker's original epidemiological studies were generalized as the Barker hypothesis and extended as the Developmental Origins of Health and Disease (DOHaD) theory. Barker et al. proposed that low birthweight (LBW) was associated with the occurrence of various noncommunicable diseases (NCDs) later in life. In other words, LBW itself is associated with the development of NCDs. This led to the DOHaD theory which proposed that an organism may have a specific period of developmental plasticity that is highly sensitive to the factors in its environment, and that combinations of acquired constitution and environmental factors may adversely affect health and risk the formation of NCDs. Due to undernutrition during the fetal period, the fetus acquires an energy-saving constitution called a thrifty phenotype due to adaptations of the metabolic and endocrine systems. It has been suggested that stimuli experienced early in development can persist throughout life and induce permanent physiological changes that predispose to NCDs. It has since become clear that the adverse environmental effects during the prenatal period are also intergenerationally and transgenerationally inherited, affecting the next generation. It has been shown that nutritional interventions such as methyldonner and epigenome editing can restore some of the impaired functions and reduce the risk of developing some diseases in the next generation. This review thus outlines the mechanisms underlying various disease risk formations and their genetic programs for the next generation, which are being elucidated through studies based on our fetal undernutrition rat models.

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“…Additionally, mGPDH and complex IV have also been considered targets of metformin in animal experiments ( Madiraju et al, 2014 ; LaMoia et al, 2022 ), and more targets have been found in the research into the actions of metformin in mitochondria ( Pecinova et al, 2019 ; MacDonald et al, 2021 ). LncRNAs regulated by metformin potentially affect mitochondrial function; clinical research on DNA methylation in plasma from metformin-treated patients with T2DM showed that 57 lncRNA-associated DNA methylation regions were found, which included the mitochondrial ATP synthase-coupling factor 6 (ATP5J) ( Solomon et al, 2020 ), suggesting that metformin may regulate ATP5J through lncRNAs. In addition, metformin increases GAS5 expression in HepG2 cells and the plasma of patients with T2DM ( Parvar et al, 2023 ), and elevated GAS5 decreases mitochondrial tricarboxylic acid flux by disrupting the metabolic enzyme tandem of the tricarboxylic acid cycle ( Sang et al, 2021 ), providing another explanation for the mitochondrial inhibition effects of metformin.…”

Section: The Anti-diabetic Action Of Metformin Mediated By Lncrnasmentioning

confidence: 99%

The anti-diabetic effects of metformin are mediated by regulating long non-coding RNA

Chang,

Li,

2023

Front. Pharmacol.

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Type 2 diabetes (T2D) is a metabolic disease with complex etiology and mechanisms. Long non-coding ribonucleic acid (LncRNA) is a novel class of functional long RNA molecules that regulate multiple biological functions through various mechanisms. Studies in the past decade have shown that lncRNAs may play an important role in regulating insulin resistance and the progression of T2D. As a widely used biguanide drug, metformin has been used for glucose lowering effects in clinical practice for more than 60 years. For diabetic therapy, metformin reduces glucose absorption from the intestines, lowers hepatic gluconeogenesis, reduces inflammation, and improves insulin sensitivity. However, despite being widely used as the first-line oral antidiabetic drug, its mechanism of action remains largely elusive. Currently, an increasing number of studies have demonstrated that the anti-diabetic effects of metformin were mediated by the regulation of lncRNAs. Metformin-regulated lncRNAs have been shown to participate in the inhibition of gluconeogenesis, regulation of lipid metabolism, and be anti-inflammatory. Thus, this review focuses on the mechanisms of action of metformin in regulating lncRNAs in diabetes, including pathways altered by metformin via targeting lncRNAs, and the potential targets of metformin through modulation of lncRNAs. Knowledge of the mechanisms of lncRNA modulation by metformin in diabetes will aid the development of new therapeutic drugs for T2D in the future.

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Genome-Wide DNA Methylation and LncRNA-Associated DNA Methylation in Metformin-Treated and -Untreated Diabetes

Cited by 7 publications

References 39 publications

Association of nutritional glycaemic indices with global DNA methylation patterns: results from the Moli-sani cohort

Association of nutritional glycaemic indices with global DNA methylation patterns: results from the Moli-sani cohort

Prevention of transgenerational transmission of disease susceptibility through perinatal intervention

The anti-diabetic effects of metformin are mediated by regulating long non-coding RNA

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