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Background <p>Type 1 diabetes (T1D) is an autoimmune disease that destroys insulin-producing β-cells. Extracellular vesicles (EVs), including exosomes, are now recognized as important mediators of intercellular communication in immune regulation and metabolic homeostasis. Yet how immune cell-derived circulating EVs contribute to metabolic dysfunction across the disease spectrum—from preclinical to clinical T1D—has not been systematically examined.</p> Methods <p>We integrated four publicly available GEO datasets: GSE97123 (plasma-derived exosome miRNA profiling in long-duration T1D patients, <i>n</i> = 24), GSE92439 (T lymphocyte-derived exosome effects on pancreatic islets, <i>n</i> = 6), GSE316823 (ductal cell EV-mediated β-cell alterations, <i>n</i> = 8), and GSE160391 (cytokine-stressed islet and EV miRNA profiles, <i>n</i> = 48). Differential expression analysis was performed using Welch’s <i>t</i>-test with Benjamini-Hochberg correction. Pathway enrichment, EV marker characterization, and cross-dataset integration were carried out to identify convergent mechanisms.</p> Results <p>In GSE97123, 292 differentially expressed miRNAs (<i>p</i> &lt; 0.05) were identified in circulating exosomes from T1D patients compared with controls, with upregulation of pro-inflammatory mediators including miR-155-5p and miR-146a-5p. In GSE92439, T lymphocyte-derived exosomes altered 8,189 genes in pancreatic islets, with changes in insulin secretion, apoptosis, and immune recognition pathways. In GSE316823, cytokine-stimulated ductal cell EVs induced 599 differentially expressed genes in β-cells, with notable upregulation of HLA class I molecules (HLA-A, HLA-B, HLA-C) and inflammatory chemokines (CXCL9, CXCL10, CXCL11, IDO1, GBP4). In GSE160391, cytokine stress caused distinct miRNA packaging into EVs versus islet fractions, with miR-155-5p and miR-146a-5p as the only two miRNAs consistently upregulated in both compartments across sexes. Cross-dataset integration showed convergent dysregulation of antigen presentation, insulin signaling, and apoptotic pathways.</p> Conclusions <p>Immune cell-derived EVs appear to transfer pro-inflammatory and metabolic-disruptive cargo to β-cells, supporting a pathogenic axis in T1D that has received limited attention. These findings suggest that EV-mediated communication could be a therapeutic target and that circulating EV miRNAs may serve as biomarkers for T1D progression.</p>

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Immune cell-derived circulating extracellular vesicles mediate metabolic dysfunction in preclinical and clinical type 1 diabetes

  • 期刊论文

  • 发表日期：

    2026年7月29日

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  • Bingbing Qu,
  • Bingjun Zeng,
  • Yurui Yuan,
  • Xiuling He,
  • Lina Ren,
  • Hang Zhu,
  • Xuanke Guan

摘要

Background

Type 1 diabetes (T1D) is an autoimmune disease that destroys insulin-producing β-cells. Extracellular vesicles (EVs), including exosomes, are now recognized as important mediators of intercellular communication in immune regulation and metabolic homeostasis. Yet how immune cell-derived circulating EVs contribute to metabolic dysfunction across the disease spectrum—from preclinical to clinical T1D—has not been systematically examined.

Methods

We integrated four publicly available GEO datasets: GSE97123 (plasma-derived exosome miRNA profiling in long-duration T1D patients, n = 24), GSE92439 (T lymphocyte-derived exosome effects on pancreatic islets, n = 6), GSE316823 (ductal cell EV-mediated β-cell alterations, n = 8), and GSE160391 (cytokine-stressed islet and EV miRNA profiles, n = 48). Differential expression analysis was performed using Welch’s t-test with Benjamini-Hochberg correction. Pathway enrichment, EV marker characterization, and cross-dataset integration were carried out to identify convergent mechanisms.

Results

In GSE97123, 292 differentially expressed miRNAs (p < 0.05) were identified in circulating exosomes from T1D patients compared with controls, with upregulation of pro-inflammatory mediators including miR-155-5p and miR-146a-5p. In GSE92439, T lymphocyte-derived exosomes altered 8,189 genes in pancreatic islets, with changes in insulin secretion, apoptosis, and immune recognition pathways. In GSE316823, cytokine-stimulated ductal cell EVs induced 599 differentially expressed genes in β-cells, with notable upregulation of HLA class I molecules (HLA-A, HLA-B, HLA-C) and inflammatory chemokines (CXCL9, CXCL10, CXCL11, IDO1, GBP4). In GSE160391, cytokine stress caused distinct miRNA packaging into EVs versus islet fractions, with miR-155-5p and miR-146a-5p as the only two miRNAs consistently upregulated in both compartments across sexes. Cross-dataset integration showed convergent dysregulation of antigen presentation, insulin signaling, and apoptotic pathways.

Conclusions

Immune cell-derived EVs appear to transfer pro-inflammatory and metabolic-disruptive cargo to β-cells, supporting a pathogenic axis in T1D that has received limited attention. These findings suggest that EV-mediated communication could be a therapeutic target and that circulating EV miRNAs may serve as biomarkers for T1D progression.