Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

El‐Osta, Assam; Brasacchio, Daniella; Yao, Dachun; Pocai, Alessandro; Jones, Peter L.; Roeder, Robert G.; Cooper, Mark E.; Brownlee, Michael

doi:10.1084/jem.20081188

Cited by 938 publications

(780 citation statements)

References 34 publications

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“…As an example, after a transient glucose level increase NFκB transcriptional activity is enhanced and maintained high through H3K9 demethylation of its promoter (El Osta et al, 2008;Brasacchio et al, 2009). On the other hand, lifestyle factors known to promote type 2 diabetes are associated with a local and/or systemic inflammatory reaction.…”

Section: Environmental Influencementioning

confidence: 99%

“…On the other hand, lifestyle factors known to promote type 2 diabetes are associated with a local and/or systemic inflammatory reaction. Likewise, high glucose levels increase mitochondrial and respiratory activity and give rise to enhanced release of superoxide anions (El Osta et al, 2008). This oxidative stress induces the expression of pro-inflammatory cytokines, such as IL-6 and TNF-α, through signaling cascades involving JNK, MAP-kinases, and transcription factors, such as NFκB and AP-1 (Kempf et al, 2007).…”

Section: Environmental Influencementioning

confidence: 99%

“…Some of these changes have been found in the promoter of the nuclear factor κB (NFκB) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, and are a cause of long-lasting increase in p65 gene expression (El-Osta et al, 2008). The phenomenon by which diabetes complications persist and progress after glycemic recovery is achieved is called metabolic memory.…”

Section: Hyperglycemiamentioning

confidence: 99%

See 2 more Smart Citations

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Milagro

Mansego

Miguel

et al. 2013

Molecular Aspects of Medicine

247

161

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Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding of the importance of the inheritance of these epigenetic marks.

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Section: Environmental Influencementioning

confidence: 99%

Section: Environmental Influencementioning

confidence: 99%

Section: Hyperglycemiamentioning

confidence: 99%

See 1 more Smart Citation

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Milagro

Mansego

Miguel

et al. 2013

Molecular Aspects of Medicine

247

161

View full text Add to dashboard Cite

show abstract

“…There is ample evidence that in vitro exposure of endothelial or mononuclear cells to high glucose concentrations (usually ≥10 mmol/l) induces the expression of inflammation-associated genes, such as those coding for IL-6, IL-8, monocyte chemoattractant protein-1 and several adhesion molecules [5]. One straightforward mechanistic explanation is that there is more substrate for mitochondrial activity as a consequence of increased glucose influx, and that increased respiratory activity gives rise to enhanced release of superoxide anions [6]. However, other studies suggest that glucose-induced superoxide formation stems from glucose-6-phosphate dehydrogenase and phosphokinase C-dependent activation of NAD(P)H oxidase [7].…”

Section: Introductionmentioning

confidence: 99%

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

Kolb¹,

2009

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The recent major increase in the global incidence of type 2 diabetes suggests that most cases of this disease are caused by changes in environment and lifestyle. All major risk factors for type 2 diabetes (overnutrition, low dietary fibre, sedentary lifestyle, sleep deprivation and depression) have been found to induce local or systemic low-grade inflammation that is usually transient or milder in individuals not at risk for type 2 diabetes. By contrast, inflammatory responses to lifestyle factors are more pronounced and prolonged in individuals at risk of type 2 diabetes and appear to occur also in the pancreatic islets. Chronic low-grade inflammation will eventually lead to overt diabetes if counter-regulatory circuits to inflammation and metabolic stress are compromised because of a genetic and/or epigenetic predisposition. Hence, it is not the lifestyle change per se but a deficient counter-regulatory response in predisposed individuals which is crucial to disease pathogenesis. Novel approaches of intervention may target these deficient defence mechanisms.

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“…Rare mutation of GLO1 in the human population is embryonically lethal in homozygous inheritance with increased risk of severe neurological disorders in heterozygous inheritance [18]. Glo1 knockout mice have otherwise been elusive and rather a mouse strain with Glo1 deficiency was developed by viral insertion of a vector expressing Glo1 siRNA [19]. Silencing and chemical inhibition of Glo1 in mice was linked to increased vascular disease [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

Shafie

Xue

Barker

et al. 2016

Biochemical Journal

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Glyoxalase 1 (Glo1) is a cytoplasmic enzyme with a cytoprotective function linked to metabolism of the cytotoxic side product of glycolysis, methylglyoxal (MG). It prevents dicarbonyl stress — the abnormal accumulation of reactive dicarbonyl metabolites, increasing protein and DNA damage. Increased Glo1 expression delays ageing and suppresses carcinogenesis, insulin resistance, cardiovascular disease and vascular complications of diabetes and renal failure. Surprisingly, gene trapping by the International Mouse Knockout Consortium (IMKC) to generate putative Glo1 knockout mice produced a mouse line with the phenotype characterised as normal and healthy. Here, we show that gene trapping mutation was successful, but the presence of Glo1 gene duplication, probably in the embryonic stem cells (ESCs) before gene trapping, maintained wild-type levels of Glo1 expression and activity and sustained the healthy phenotype. In further investigation of the consequences of dicarbonyl stress in ESCs, we found that prolonged exposure of mouse ESCs in culture to high concentrations of MG and/or hypoxia led to low-level increase in Glo1 copy number. In clinical translation, we found a high prevalence of low-level GLO1 copy number increase in renal failure where there is severe dicarbonyl stress. In conclusion, the IMKC Glo1 mutant mouse is not deficient in Glo1 expression through duplication of the Glo1 wild-type allele. Dicarbonyl stress and/or hypoxia induces low-level copy number alternation in ESCs. Similar processes may drive rare GLO1 duplication in health and disease.

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Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia

Cited by 938 publications

References 34 publications

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

The global diabetes epidemic as a consequence of lifestyle-induced low-grade inflammation

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

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