Dataset Information

Effect of excess weight and insulin resistance on DNA methylation in prepubertal children.

ABSTRACT: Epigenetic mechanisms, such as DNA methylation, regulate gene expression and play a role in the development of insulin resistance. This study evaluates how the BMI z-score (BMIz) and the homeostatic model assessment of insulin resistance (HOMA-IR), alone or in combination, relate to clinical outcomes and DNA methylation patterns in prepubertal children. DNA methylation in peripheral blood mononuclear cells (PBMCs) and clinical outcomes were measured in a cohort of 41 prepubertal children. Children with higher HOMA-IR had higher blood pressure and plasma lactate levels while children with higher BMIz had higher triglycerides levels. Moreover, the DNA methylation analysis demonstrated that a 1 unit increase in the BMIz was associated with a 0.41 (95% CI: 0.29, 0.53) increase in methylation of a CpG near the PPP6R2 gene. This gene is important in the regulation of NF-kB expression. However, there was no strong evidence that the BMIz and the HOMA-IR were synergistically related to any clinical or DNA methylation outcomes. In summary, the results suggest that obesity and insulin resistance may impact metabolic health both independently in prepubertal children. In addition, obesity also has an impact on the DNA methylation of the PPP6R2 gene. This may be a novel underlying starting point for the systemic inflammation associated with obesity and insulin resistance, in this population.

SUBMITTER: Barbosa P

PROVIDER: S-EPMC9120504 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Effect of excess weight and insulin resistance on DNA methylation in prepubertal children.

Barbosa Pedro P Landes Reid D RD Graw Stefan S Byrum Stephanie D SD Bennuri Sirish S Delhey Leanna L Randolph Chris C MacLeod Stewart S Reis Andreia A Børsheim Elisabet E Rose Shannon S Carvalho Eugenia E

Scientific reports 20220519 1

Epigenetic mechanisms, such as DNA methylation, regulate gene expression and play a role in the development of insulin resistance. This study evaluates how the BMI z-score (BMIz) and the homeostatic model assessment of insulin resistance (HOMA-IR), alone or in combination, relate to clinical outcomes and DNA methylation patterns in prepubertal children. DNA methylation in peripheral blood mononuclear cells (PBMCs) and clinical outcomes were measured in a cohort of 41 prepubertal children. Childr ...[more]

PMID: 35589784

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Project description:ImportanceAlthough benefits have been reported for most exercise modalities, the most effective exercise approaches for reducing insulin resistance in children and adolescents with excess weight and the optimal exercise dose remain unknown.ObjectiveTo compare exercise training modalities and their association with changes in insulin resistance markers among children and adolescents with excess weight and to establish the optimal exercise dose.Data sourcesFor this systematic review and network meta-analysis, 6 electronic databases (PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Scopus, Web of Science, and CINAHL) were searched for studies from inception to April 1, 2023.Study selectionRandomized clinical trials (ie, randomized controlled trials and randomized trials without a control group) were included if they reported outcomes associated with aerobic training, resistance training, high-intensity interval training (HIIT), or a combination of these interventions.Data extraction and synthesisData extraction for this systematic review was conducted following a network meta-analysis extension of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline. Effect sizes were calculated as the mean difference (MD) with 95% CI using random-effects inverse-variance models with the Hartung-Knapp-Sidik-Jonkman method. The hierarchy of competing interventions was defined using the surface under the cumulative ranking curve. The Cochrane Risk-of-Bias tool, version 2 (RoB2), was used to independently assess the risk of bias of the included studies. The certainty of evidence in consistent networks was assessed using the Grading of Recommendation, Assessment, Development and Evaluation approach. The study protocol was prospectively registered with PROSPERO. Data analyses were conducted between May and June 2023.Main outcomes and measuresThe primary outcomes were fasting glucose, insulin, and homeostatic model assessment for insulin resistance (HOMA-IR).ResultsThis analysis included 55 studies with a total of 3051 children and adolescents (mean [SD] age, 13.5 [2.3] years; 1537 girls [50.4%] and 1514 boys [49.6%]). Exercise was associated with reductions in fasting insulin (MD, -4.38 μU/mL [95% CI, -5.94 to -2.82 μU/mL]) and HOMA-IR (MD, -0.87 [95% CI, -1.20 to -0.53]). A nonlinear association in both markers was observed, with a required minimal exercise dosage of approximately 900 to 1200 metabolic equivalent of task minutes per week, especially in children and adolescents with insulin resistance at baseline. Combination HIIT and resistance training and concurrent training were the most effective approaches for reducing insulin resistance markers. On average, the certainty of evidence varied from low to moderate.Conclusions and relevanceThese findings underscore the role of exercise interventions in enhancing insulin resistance markers among children and adolescents with overweight and obesity. It is advisable to include resistance exercises alongside aerobic and HIIT programs for a minimum of two to three 60-minute sessions per week.

Project description:BACKGROUND: The aim of this study was to investigate sex differences and associations of high molecular weight (HMW) adiponectin, leptin and proinflammatory adipokines, individually or in combinations, with adiposity and insulin resistance (IR) measures in prepubertal childhood. METHODOLOGY: We studied 305 prepubertal children (boys/girls: 144/161; Tanner stage 1; age: 5-13 yr), included in a cohort of 44,231 adolescents who participated in an extensive Italian school-based survey. According to Cole's criteria, 105 individuals were lean (L; boys/girls: 59/46), 60 overweight (OW; boys/girls: 32/28) and 140 obese (OB; boys/girls: 70/70). Measurements comprised total and HMW adiponectin, leptin, as well as a panel of proinflammatory adipokines/chemokines associated with diabetes risk. PRINCIPAL FINDINGS: Leptin-, and the leptin-to-HMW adiponectin ratio (L/HMW)-, increased progressively (p<0.0001) from L to OW to OB boys and girls. When compared with L peers, OW and OB girls exhibited lower (p<0.001) HMW adiponectin levels, while in boys the HMW multimers did not differ significantly across the BMI-stratified groups. OB girls displayed higher (p<0.05) IL-8, IL-18, monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1 levels (sICAM-1) than L girls, whereas increased macrophage migration inhibitory factor (MIF) concentrations in OB vs OW boys were seen. HMW adiponectin (negatively), leptin or inflammatory markers (positively) correlated with adiposity and IR measures. In multivariate models, leptin represented a strong and independent determinant of HOMA-IR (R(2) 0.378; p<0.01). Adjustment for age, BMI(z-score), lipids and inflammatory mediators abolished the association between leptin and HOMA-IR in boys, while in girls leptin remained still a significant predictor of IR (R(2) 0.513; p<0.01). Finally, in both sexes, the joint effect of the L/HMW did not improve the prediction of basal IR as compared with leptin levels alone, which were mainly explained by the BMI(z-score.) CONCLUSIONS: In prepubertal children, leptin emerges as a sex-independent discrimination marker of adiposity degree and as a useful, sex-associated predictor of the systemic insulin resistance.

Project description:Childhood obesity, and specifically its metabolic complications, are related to deficient antioxidant capacity and oxidative stress. Erythrocytes are constantly exposed to multiple sources of oxidative stress; hence, they are equipped with powerful antioxidant mechanisms requiring permanent reducing power generation and turnover. Glucose-6-phosphate dehydrogenase (G6PDH) and 6-phosphogluconate dehydrogenase (6PGDH) are two key enzymes on the pentose phosphate pathway. Both enzymes supply reducing power by generating NADPH, which is essential for maintaining the redox balance within the cell and the activity of other antioxidant enzymes. We hypothesized that obese children with insulin resistance would exhibit blunted G6PDH and 6PGDH activities, contributing to their erythrocytes' redox status imbalances. We studied 15 control and 24 obese prepubertal children, 12 of whom were insulin-resistant according to an oral glucose tolerance test (OGTT). We analyzed erythroid malondialdehyde (MDA) and carbonyl group levels as oxidative stress markers. NADP+/NADPH and GSH/GSSG were measured to determine redox status, and NADPH production by both G6PDH and 6PGDH was assayed spectrophotometrically to characterize pentose phosphate pathway activity. Finally, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) activities were also assessed. As expected, MDA and carbonyl groups levels were higher at baseline and along the OGTT in insulin-resistant children. Both redox indicators showed an imbalance in favor of the oxidized forms along the OGTT in the insulin-resistant obese group. Additionally, the NADPH synthesis, as well as GR activity, were decreased. H2O2 removing enzyme activities were depleted at baseline in both obese groups, although after sugar intake only metabolically healthy obese participants were able to maintain their catalase activity. No change was detected in SOD activity between groups. Our results show that obese children with insulin resistance present higher levels of oxidative damage, blunted capacity to generate reducing power, and hampered function of key NADPH-dependent antioxidant enzymes.

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Effect of excess weight and insulin resistance on DNA methylation in prepubertal children.

Publications

Effect of excess weight and insulin resistance on DNA methylation in prepubertal children.

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