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Iron overload is related to elevated blood glucose levels in obese children and aggravates high glucose-induced endothelial cell dysfunction in vitro
  1. Wei Wu1,2,
  2. Jinna Yuan1,
  3. Yu Shen3,
  4. Yunxian Yu3,
  5. Xuefeng Chen1,
  6. Li Zhang1,
  7. Ke Huang1,
  8. Jianying Zhan1,
  9. Guan-Ping Dong1,2,
  10. Junfen Fu1
  1. 1Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  2. 2National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  3. 3Department of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  1. Correspondence to Dr Guan-Ping Dong; dgpxlx{at}zju.edu.cn

Abstract

Introduction This study was performed to investigate the role of iron overload in the early stage of hyperglycemia-induced vascular functional impairment.

Research design and methods A total of 196 obese children were enrolled, and data regarding ferritin levels, blood glucose levels, intima-media thickness of carotid arteries, liver function and fibrosis index, hemoglobin, blood pressure, blood lipids, and inflammation indicators were collected. Ferritin levels were compared with a control group, which consisted of 148 healthy non-obese children who were age-matched and gender-matched. Endothelial cells were cultured in high glucose medium and supplemented with ferric citrate with or without iron remover (deferoxamine), a reducing agent (N-acetyl-cysteine), or a nuclear factor-κB (NF-κB) inhibitor (BAY 11-7082). Apoptosis, oxidative stress, nitric oxide levels, and endothelin content were evaluated. DNA microarray analysis was performed to analyze the expression of genes in the NF-κB signaling pathway.

Results Obese children have significantly higher ferritin levels compared with the control group. Ferritin level was positively correlated with hemoglobin and was related to metabolic disorders, including impaired glucose tolerance, higher blood pressure, dyslipidemia, and impaired hepatic function. Endothelial cells treated with ferric citrate showed a significantly higher rate of apoptosis, higher levels of oxidative stress, and impaired vasomotor function under high glucose conditions. The above effects were rescued by treatment with an iron remover, reducing agent, or NF-κB inhibitor. Further, detection of phosphorylated-p65 distribution in cells confirmed activation of the NF-κB pathway. DNA microarrays and subsequent gene oncology enrichment analyses revealed the main processes activated in cells.

Conclusion Increased ferritin levels are related to impaired glucose tolerance and other metabolic disorders in obese children. At the cellular level, iron overload aggravated the endothelial cell dysfunction caused by high glucose.

  • blood glucose
  • endothelial cells
  • pediatric obesity
  • oxidative stress
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Footnotes

  • Contributors WW: design of the work, data collection, data analysis and interpretation, drafting the article, final approval of the version to be published. JY: data collection, data analysis and interpretation, final approval of the version to be published. YS, YY: data analysis and interpretation, final approval of the version to be published. XC, LZ, KH, JZ: data collection, final approval of the version to be published. G-PD: conception of the work, data collection, critical revision of the article, final approval of the version to be published. JF: critical revision of the article, final approval of the version to be published.

  • Funding This study was supported by the National Key Research and Development Program of China (no 2016YFC1305301, to JF), National Natural Science Foundation of China (no 81471056, to WW), Research Fund of Zhejiang Major Medical and Health Science and Technology & National Ministry of Health (WKJ-ZJ-1804, to WW), and Zhejiang Province Natural Science Foundation-Zhejiang Society for Mathematical Medicine (LSZ19H070001, to WW).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the ethical committee of Children’s Hospital, Zhejiang University, School of Medicine (2016IRB-018).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data from this study are available upon reasonable request from the corresponding author.

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