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Genetics/Genomes/Proteomics/Metabolomics
Original research
Heredity of type 2 diabetes confers increased susceptibility to oxidative stress and inflammation
  1. Sonia Baig1,
  2. Muhammad Shabeer1,
  3. Ehsan Parvaresh Rizi1,
  4. Madhur Agarwal1,2,
  5. Michelle H Lee1,
  6. Delicia Shu Qin Ooi3,4,
  7. Chelsea Chia5,6,
  8. Nweni Aung1,
  9. Geelyn Ng1,
  10. Yvonne Teo1,
  11. Vanna Chhay1,
  12. Faidon Magkos7,
  13. Antonio Vidal-Puig8,
  14. Raymond C S Seet1,5,
  15. Sue-Anne Toh1,9
  1. 1Medicine, National University of Singapore, Singapore
  2. 2Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA
  3. 3Department of Paediatrics, National University of Singapore, Singapore
  4. 4Khoo Teck Puat-National University Children’s Medical Institute, National University Health System, Singapore
  5. 5Medicine, National University Health System, Singapore
  6. 6School of Medicine, Trinity College Dublin, Dublin, Ireland
  7. 7Section for Obesity Research, Department of Nutrition, Exercise and Sports, University of Copenhagen, København, Denmark
  8. 8Department of Clinical Biochemistry, University of Cambridge School of Clinical Medicine, Cambridge, Cambridgeshire, UK
  9. 9Department of Endocrinology, Diabetes and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
  1. Correspondence to Dr Sue-Anne Toh; mdcsates{at}nus.edu.sg

Abstract

Introduction and objective Heredity of type 2 diabetes mellitus (T2DM) is associated with greater risk for developing T2DM. Thus, individuals who have a first-degree relative with T2DM (FDRT) provide a natural model to study factors of susceptibility towards development of T2DM, which are poorly understood. Emerging key players in T2DM pathophysiology such as adverse oxidative stress and inflammatory responses could be among possible mechanisms that predispose FDRTs to develop T2DM. Here, we aimed to examine the role of oxidative stress and inflammatory responses as mediators of this excess risk by studying dynamic postprandial responses in FDRTs.

Research design and methods In this open-label case-control study, we recruited normoglycemic men with (n=9) or without (n=9) a family history of T2DM. We assessed plasma glucose, insulin, lipid profile, cytokines and F2-isoprostanes, expression levels of oxidative and inflammatory genes/proteins in circulating mononuclear cells (MNC), myotubes and adipocytes at baseline (fasting state), and after consumption of a carbohydrate-rich liquid meal or insulin stimulation.

Results Postprandial glucose and insulin responses were not different between groups. Expression of oxidant transcription factor NRF2 protein (p<0.05 for myotubes) and gene (pgroup=0.002, ptime×group=0.016), along with its target genes TXNRD1 (pgroup=0.004, ptime×group=0.007), GPX3 (pgroup=0.011, ptime×group=0.019) and SOD-1 (pgroup=0.046 and ptime×group=0.191) was upregulated in FDRT-derived MNC after meal ingestion or insulin stimulation. Synergistically, expression of target genes of inflammatory transcription factor nuclear factor kappa B such as tumor necrosis factor alpha (pgroup=0.001, ptime×group=0.007) was greater in FDRT-derived MNC than in non-FDRT-derived MNC after meal ingestion or insulin stimulation.

Conclusions Our findings shed light on how heredity of T2DM confers increased susceptibility to oxidative stress and inflammation. This could provide early insights into the underlying mechanisms and future risk of FDRTs for developing T2DM and its associated complications.

  • family history of type 2 diabetes
  • oxidative stress
  • inflammation
  • myotubes
  • adipocytes
  • mononuclear cells
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjdrc-2019-000945

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    Footnotes

    • Contributors SB, MS and EPR contributed to the study execution, acquisition, analyses and interpretation of data, and manuscript preparation. SB, MS, MA, DSQO, NA, GN, VC, and YT performed various experiments/analyses (MNC isolation, adipocyte/myotube culture, gene/protein expression assay, glutathione assay, and F2-isoprostane assay). AVP and SAT contributed to the grant proposal. FM, MHL, DSQO, CC, RCSS and AVP contributed to critical revision of the manuscript. SAT contributed to the conception and design of the work and interpretation of data and critically revised the manuscript. SB, MS and SAT are the guarantors of this work, and as such, had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    • Funding This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its NUHS-CG Metabolic In-Vitro Models Core Seed Funding (NMRC/CG/013/2013), the Clinician Scientist Award Grant (NMRC/CSA/034/2012), and the Cambridge-NUHS Seed Fund (NUHSRO/2012/067/Cambridge/03). AV-P is funded by the British Heart Foundation.

    • Competing interests None declared.

    • Patient consent for publication Not required.

    • Ethics approval The study was approved by Singapore’s National Healthcare Group Domain Specific Review Board (Ref No: C/2013/00902), and all procedures followed the Singapore Good Clinical Practice guideline and the principles of the 2013 Declaration of Helsinki. All participants provided written consent before participation in this study.

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

    • Data availability statement All data generated or analyzed during this study are included in the published article (and its online supplementary files). No applicable resources were generated or analyzed during the current study, except the following: Genome-Tissue Expression (GTEx) repository (https://www.gtexportal.org/home/); East-Asian reference panel from the 1000 Genomes database (http://grch37.ensembl.org/index.html).