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Background <p>Small extracellular vesicles (sEV) mediate intercellular communication in gestational diabetes mellitus (GDM). However, the mechanisms by which GDM-derived placental sEV induce pancreatic islet cell injury remain unclear. Here, we investigated the functions and underlying mechanisms of placenta-derived sEV (Pd-sEV)-associated miRNAs in GDM.</p> Methods <p>Pregnant women with normal glucose tolerance (NGT) or GDM were recruited, and clinical characteristics and inflammatory indices were assessed. Pd-sEVs were isolated and characterized. The effects of GDM-derived Pd-sEVs on insulin secretion and apoptosis in β-cells were evaluated. Following miRNA sequencing and diagnostic assessment, bioinformatic analysis identified downstream targets. Finally, miRNA mimics, specific inhibitors, and Sirtuin 1 (SIRT1) overexpression, and enzymatic activity assays were used to validate the regulatory mechanisms.</p> Results <p>GDM patients exhibited a sustained inflammatory state and significantly elevated levels of Pd-sEVs. These GDM-derived Pd-sEVs were efficiently internalized by β-cells, impairing glucose-stimulated insulin secretion (GSIS) and inducing apoptosis. Sequencing revealed selective alterations in the miRNA profile in GDM-sEV, with 4 significantly upregulated and 11 downregulated miRNAs. Among these, miR-520d-5p showed the most robust alteration in vivo and demonstrated the highest diagnostic sensitivity and specificity. Notably, circulating miR-520d-5p levels positively correlated with 75-g oral glucose tolerance test (OGTT) glucose levels. Bioinformatics analysis identified 707 high-confidence target genes, with SIRT1 identified as a core gene. Additionally, miR-520d-5p mimics or GDM-derived Pd-sEVs significantly reduced SIRT1 levels and impaired its enzymatic deacetylation activity. Mechanistically, miR-520d-5p directly targeted the SIRT1 3′-UTR, while miR-520d-5p inhibition or SIRT1 overexpression significantly attenuated the Pd-sEV-induced functional defects.</p> Conclusions <p>This study supports that miR-520d-5p shuttled by Pd-sEVs mediates pancreatic β-cell injury in GDM via targeting SIRT1. These findings suggest that Pd-sEV-associated miR-520d-5p serves as a promising diagnostic biomarker, and targeting the miR-520d-5p/SIRT1 axis offers a potential therapeutic strategy for preserving β-cell function in GDM.</p>

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Placenta-derived small extracellular vesicles transfer miR-520d-5p to mediate pancreatic β-cell injury in gestational diabetes mellitus by targeting SIRT1

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Qiang Ma,
  • Luxin Dai,
  • Fang Chen,
  • Suping Li,
  • Ziwen Zhang,
  • Ling Ai,
  • Jinhua Dong

摘要

Background

Small extracellular vesicles (sEV) mediate intercellular communication in gestational diabetes mellitus (GDM). However, the mechanisms by which GDM-derived placental sEV induce pancreatic islet cell injury remain unclear. Here, we investigated the functions and underlying mechanisms of placenta-derived sEV (Pd-sEV)-associated miRNAs in GDM.

Methods

Pregnant women with normal glucose tolerance (NGT) or GDM were recruited, and clinical characteristics and inflammatory indices were assessed. Pd-sEVs were isolated and characterized. The effects of GDM-derived Pd-sEVs on insulin secretion and apoptosis in β-cells were evaluated. Following miRNA sequencing and diagnostic assessment, bioinformatic analysis identified downstream targets. Finally, miRNA mimics, specific inhibitors, and Sirtuin 1 (SIRT1) overexpression, and enzymatic activity assays were used to validate the regulatory mechanisms.

Results

GDM patients exhibited a sustained inflammatory state and significantly elevated levels of Pd-sEVs. These GDM-derived Pd-sEVs were efficiently internalized by β-cells, impairing glucose-stimulated insulin secretion (GSIS) and inducing apoptosis. Sequencing revealed selective alterations in the miRNA profile in GDM-sEV, with 4 significantly upregulated and 11 downregulated miRNAs. Among these, miR-520d-5p showed the most robust alteration in vivo and demonstrated the highest diagnostic sensitivity and specificity. Notably, circulating miR-520d-5p levels positively correlated with 75-g oral glucose tolerance test (OGTT) glucose levels. Bioinformatics analysis identified 707 high-confidence target genes, with SIRT1 identified as a core gene. Additionally, miR-520d-5p mimics or GDM-derived Pd-sEVs significantly reduced SIRT1 levels and impaired its enzymatic deacetylation activity. Mechanistically, miR-520d-5p directly targeted the SIRT1 3′-UTR, while miR-520d-5p inhibition or SIRT1 overexpression significantly attenuated the Pd-sEV-induced functional defects.

Conclusions

This study supports that miR-520d-5p shuttled by Pd-sEVs mediates pancreatic β-cell injury in GDM via targeting SIRT1. These findings suggest that Pd-sEV-associated miR-520d-5p serves as a promising diagnostic biomarker, and targeting the miR-520d-5p/SIRT1 axis offers a potential therapeutic strategy for preserving β-cell function in GDM.