Hepatic IGF2/H19 Epigenetic Alteration Induced Glucose Intolerance in Gestational Diabetes Mellitus Offspring via FoxO1 Mediation

Jiang, Ying; Zhu, Hong; Chen, Zi; Yu, Yi-Chen; Guo, Xiaohan; Chen, Yuan; Chen, Bang-Wu; Sagnelli, Matthew; Xu, Dong; Zhao, Baihui; Luo, Qiong

doi:10.3389/fendo.2022.844707

Cited by 14 publications

(8 citation statements)

References 47 publications

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“…As this region controls the H19 and IFG2 imprinting cluster, LOI is related to altered glucose metabolism and diabetes [ 50 ]. Intrauterine hyperinsulinemia changes H19DMR methylation in the foetuses which exhibited impaired glucose tolerance and insulin resistance [ 51 ]. Obesity is a risk factor for cancer in general and is associated with an increased risk of invasive penile cancer, inducing chronic inflammation and insulin resistance [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Hypomethylation at H19DMR in penile squamous cell carcinoma is not related to HPV infection

da Silva Santos,

Pascoalino Pinheiro,

Gustavo Hirth

et al. 2024

Epigenetics

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Penile squamous cell carcinoma (SCC) is a rare and aggressive tumour mainly related to lifestyle behaviour and human papillomavirus (HPV) infection. Environmentally induced loss of imprinting (LOI) at the H19 differentially methylated region (H19DMR) is associated with many cancers in the early events of tumorigenesis and may be involved in the pathogenesis of penile SCC. We sought to evaluate the DNA methylation pattern at H19DMR and its association with HPV infection in men with penile SCC by bisulfite sequencing (bis-seq). We observed an average methylation of 32.2% ± 11.6% at the H19DMR of penile SCC and did not observe an association between the p16 INK4a + ( p = 0.59) and high-risk HPV+ ( p = 0.338) markers with methylation level. The average methylation did not change according to HPV positive for p16 INK4a + or hrHPV+ (35.4% ± 10%) and negative for both markers (32.4% ± 10.1%) groups. As the region analysed has a binding site for the CTCF protein, the hypomethylation at the surrounding CpG sites might alter its insulator function. In addition, there was a positive correlation between intense polymorphonuclear cell infiltration and hypomethylation at H19DMR ( p = 0.035). Here, we report that hypomethylation at H19DMR in penile SCC might contribute to tumour progression and aggressiveness regardless of HPV infection.

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Section: Discussionmentioning

confidence: 99%

Hypomethylation at H19DMR in penile squamous cell carcinoma is not related to HPV infection

da Silva Santos,

Pascoalino Pinheiro,

Gustavo Hirth

et al. 2024

Epigenetics

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“…Therefore, the upregulation of IGF2 in response to high-glucose conditions may be a feedback loop to increase the utilization of glucose and reduce the blood glucose level, which probably contributes to weight gain. A previous paper ( 26 ) indicated that male offspring of GDM mice have lower expression of IGF2 in the liver, and they show more severe glucose intolerance and insulin resistance than female offspring. Elevated IGF2 levels may be beneficial in stabilizing blood glucose concentrations, such as in the intrauterine hyperglycemic environment in women with GDM, but the consequence of this process affecting weight gain probably leads to macrosomia, which is an adverse pregnancy outcome.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of IGF2 affects mouse weight and glycolipid metabolism and IGF2 is positively related to macrosomia

et al. 2023

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ObjectiveTo investigate the effects of insulin-like growth factor 2 (IGF2) on growth and glycolipid metabolism, as well as the underlying mechanism.MethodsA mouse model of IGF2 overexpression was constructed to measure weight gain before adulthood, to obtain the values of adult glycolipid metabolism indicators in the peripheral blood and to detect the expression of genes in the IGF2 signaling pathway in different mouse tissues. The present study also explored the independent association between the IGF2 gene and macrosomia by detecting and comparing the expression levels of IGF2 mRNA/H19 RNA in maternal peripheral blood and fetal cord blood of 26 human pregnancies.ResultsIn the mouse model, weights of the IGF2-overexpressing mice were significantly higher than those of the control mice at the age of 5-10 weeks. The glucose concentration, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels of IGF2-overexpressing mice were significantly lower than those of wild-type (WT) mice. Compared with the WT mice, the expression of H19 was significantly decreased in the pancreas and IGF1R was significantly decreased in the muscle of mice with IGF2 overexpression. The expression levels of STAT3 and AKT2 showed significant decrease in liver, muscle and increase in muscle of IGF2-overexpressing mice, respectively. GLUT2 expression showed significant increase in liver, kidney, muscle and decrease in pancreas of mice with IGF2 overexpression. This study also found that in normal mothers with the similar clinical characteristics, IGF2 expression in the maternal peripheral blood and fetal cord blood is an independent factor influencing macrosomia. ConclusionIGF2 expression was independently correlated with the occurrence of macrosomia, and overexpression of IGF2 significantly increased the weights of mice at the age of 5-10 weeks and significantly affected the values of adult glycolipid metabolism indicators, which might be the result of changes in the IGF2-IGF1R-STAT3/AKT2-GLUT2/GLUT4 pathway. These findings might suggest that IGF2 plays an important role in growth and glycolipid metabolism during both pregnancy and postnatal development.

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“…Other mouse models of GDM have sought to confirm this finding, and also noted offspring sex-specific differences in response to maternal hyperglycaemia. While IGT was reported in both male and female offspring, only male offspring demonstrated increased birth weight, increased gluconeogenesis, increased fasting insulin and decreased insulin sensitivity ( 132 ). In contrast to findings in the pancreas, hepatic expression of IGF2 and H19 was significantly higher in male offspring, with hypermethylation reported at IGF2 -DMR0 and IGF2 -DMR1.…”

Section: Subsectionsmentioning

confidence: 99%

Multigenerational diabetes mellitus

Thornton,

Shah,

Lillycrop

et al. 2024

Front. Endocrinol.

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Gestational diabetes (GDM) changes the maternal metabolic and uterine environment, thus increasing the risk of short- and long-term adverse outcomes for both mother and child. Children of mothers who have GDM during their pregnancy are more likely to develop Type 2 Diabetes (T2D), early-onset cardiovascular disease and GDM when they themselves become pregnant, perpetuating a multigenerational increased risk of metabolic disease. The negative effect of GDM is exacerbated by maternal obesity, which induces a greater derangement of fetal adipogenesis and growth. Multiple factors, including genetic, epigenetic and metabolic, which interact with lifestyle factors and the environment, are likely to contribute to the development of GDM. Genetic factors are particularly important, with 30% of women with GDM having at least one parent with T2D. Fetal epigenetic modifications occur in response to maternal GDM, and may mediate both multi- and transgenerational risk. Changes to the maternal metabolome in GDM are primarily related to fatty acid oxidation, inflammation and insulin resistance. These might be effective early biomarkers allowing the identification of women at risk of GDM prior to the development of hyperglycaemia. The impact of the intra-uterine environment on the developing fetus, “developmental programming”, has a multisystem effect, but its influence on adipogenesis is particularly important as it will determine baseline insulin sensitivity, and the response to future metabolic challenges. Identifying the critical window of metabolic development and developing effective interventions are key to our ability to improve population metabolic health.

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Hepatic IGF2/H19 Epigenetic Alteration Induced Glucose Intolerance in Gestational Diabetes Mellitus Offspring via FoxO1 Mediation

Cited by 14 publications

References 47 publications

Hypomethylation at H19DMR in penile squamous cell carcinoma is not related to HPV infection

Hypomethylation at H19DMR in penile squamous cell carcinoma is not related to HPV infection

Overexpression of IGF2 affects mouse weight and glycolipid metabolism and IGF2 is positively related to macrosomia

Multigenerational diabetes mellitus

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