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Altered expression of long noncoding RNA MEG3 in the offspring of gestational diabetes mellitus induces impaired glucose tolerance in adulthood

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Abstract

Aim

Gestational diabetes mellitus (GDM) affects a significant number of women worldwide and has been associated with lifelong health consequences for their offspring, including increased susceptibility to obesity, insulin resistance, and type II diabetes. Recent studies have suggested that aberrant expression of the long non-coding RNA Meg3 in the liver may contribute to impaired glucose metabolism in individuals. In this study, we aimed to investigate whether intrauterine exposure to hyperglycemia affects glucose intolerance in puberty by mediating the overexpression of LncMeg3 in the liver.

Methods

To test our hypothesis, we established an animal model of intrauterine hyperglycemia to mimic GDM. The progeny was observed for phenotypic changes, and intraperitoneal glucose tolerance tests, insulin tolerance tests, and pyruvate tolerance tests were conducted to assess glucose and insulin tolerance. We also measured LncMeg3 expression in the liver using real-time quantitative PCR and examined differential methylation areas (DMRs) in the Meg3 gene using pyrophosphoric sequencing. To investigate the role of LncMeg3 in glucose tolerance, we conducted Meg3 intervention by vein tail and analyzed the changes in the phenotype and transcriptome of the progeny using bioinformatics analysis.

Results

We found that intrauterine exposure to hyperglycemia led to impaired glucose and insulin tolerance in the progeny, with a tendency toward increased fasting blood glucose in fat offspring at 16 weeks (P = 0.0004). LncMeg3 expression was significantly upregulated (P = 0.0061), DNMT3B expression downregulated (P = 0.0226), and DNMT3A (P = 0.0026), TET2 (P = 0.0180) expression upregulated in the liver. Pyrophosphoric sequencing showed hypomethylation in Meg3-DMRs (P = 0.0005). Meg3 intervention by vein tail led to a decrease in the percentage of obese and emaciated offspring (emaciation: 44% vs. 23%; obesity: 25% vs. 15%) and attenuated glucose intolerance. Bioinformatics analysis revealed significant differences in the transcriptome of the progeny, particularly in circadian rhythm and PPAR signaling pathways.

Conclusion

In conclusion, our study suggests that hypomethylation of Meg3-DMRs increases the expression of the imprinted gene Meg3 in the liver of males, which is associated with impaired glucose tolerance in GDM-F1. MEG3 interference may attenuate glucose intolerance, which may be related to transcriptional changes. Our findings provide new insights into the mechanisms underlying the long-term effects of intrauterine hyperglycemia on progeny health and highlight the potential of Meg3 as an intervention target for glucose intolerance.

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Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

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Acknowledgements

The authors thank the staff at Women’s Hospital, Zhejiang University, for the technical assistance and facility support.

Funding

This work was supported by Natural Science Foundation of Zhejiang Province (LQ20H040008) and Effect of immersive distraction therapy based on virtual reality in labor pain management, Education department, Zhejiang province (Y202146854).

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Author notes

  1. Meng Meng Yang, Juan Wei and Li Li Xu are co-first authors who contributed equally to this manuscript.

Authors and Affiliations

  1. Department of Obstetrics, Women’s Hospital, of Zhejiang University School of Medicine, Hangzhou, China

    Meng Meng Yang, Juan Wei, Li Li Xu, Yuan Chen, Min Lv, Ying Jiang & Qiong Luo

  2. The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China

    Yi Shang Yan

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Contributions

MY, JW, and LX contributed to the collection, analysis, and interpretation of data as well as manuscript preparation. YY contributed to the data collection and analysis. YC and ML contributed to the data collection. YJ and QL contributed to the study design, data interpretation, and manuscript preparation. YJ and QL is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

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Correspondence to Ying Jiang or Qiong Luo.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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This article does not contain any study with human participants. All procedures performed in this study involving animals were reviewed and approved by the Zhejiang University Animal Care and Use Committee (IACUC).

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For this study, which included only animal specimens, informed consent is not required.

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This article belongs to the topical collection Pregnancy and Diabetes, managed by Antonio Secchi and Marina Scavini.

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Yang, M., Wei, J., Xu, L. et al. Altered expression of long noncoding RNA MEG3 in the offspring of gestational diabetes mellitus induces impaired glucose tolerance in adulthood. Acta Diabetol 61, 79–90 (2024). https://doi.org/10.1007/s00592-023-02169-x

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