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Background <p>Glucagon-like peptide-1 receptor agonist (GLP-1RAs) is a potent therapy for type 2 diabetes mellitus (T2DM) and obesity, especially in patients who are resistant to long-term insulin therapy. Although microRNAs have been linked to GLP-1 signaling, their role in GLP-1RA monotherapy and combination therapy remains unclear. This review synthesizes current evidence of GLP-1RA-induced exosomal and non-exosomal miRNA changes in human and animal models of T2DM.</p> Methods <p>Scopus, PubMed/Medline, Web of Science, and Google Scholar searches returned 83 studies, of which 11 met the study eligibility criteria (PROSPERO No: CRD42024586000).</p> Results <p>Human studies showed GLP-1RA combined with metformin modulated non-exosomal <i>miR-27b</i>,<i> miR-130a</i>, and <i>miR-210a</i>, which were linked to cardiovascular health. In T2DM patients on metformin, higher baseline <i>miR-378-3p</i> or <i>miR-126-3p</i> correlated with greater HbA1c improvement after one year of GLP-1RA therapy. Notably, &gt; 5% weight loss correlated with higher baseline levels of <i>miR-15a-5p</i>. Preclinical findings suggested GLP-1RA monotherapy increased cardiovascular action via non-exosomal <i>miR-29b-3p</i>,<i> miR-34a-5p</i>,<i> miR-26a-5p</i>,<i> miR-181a-5p</i>, and <i>miR-93-5p</i>. Silencing non-exosomal <i>miR-204</i>,<i> miR-375</i>, or <i>miR-139-5p</i> augmented exendin-4/liraglutide monotherapy-induced glucose-stimulated insulin secretion. Interestingly, GLP-1RA monotherapy reduced hepatic lipid accumulation in T2DM models with comorbid NAFLD via <i>ABHD6</i> mRNA modulation by non-exosomal <i>miR-5120</i>. No clinical studies reported exosomal miRNAs, but a preclinical study linked GLP-1RA-induced exosomal <i>let-7c-2-3p</i>/<i>miR-322-3p</i> to bone protection in estrogen-deficient T2DM models.</p> Conclusion <p>GLP-1RAs, both as first-line and second-line therapies, are beneficial for T2DM complicated by obesity, NAFLD, cardio-metabolic disease, and postmenopausal osteoporosis. Longitudinal trials that incorporate innovative multi-omics approaches are essential for distinguishing their miRNA expression pattern from other anti-diabetics.</p>

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Impact of monotherapy and combination therapy with glucagon-like peptide-1 receptor agonists on exosomal and non-exosomal MicroRNA signatures in type 2 diabetes mellitus: a systematic review

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月25日

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  • Haifeng Yu,
  • Maryam Davoudi,
  • Sahar Sadegh-Nejadi,
  • Xiaolei Miao,
  • Molood Bagherieh,
  • Reza Afrisham

摘要

Background

Glucagon-like peptide-1 receptor agonist (GLP-1RAs) is a potent therapy for type 2 diabetes mellitus (T2DM) and obesity, especially in patients who are resistant to long-term insulin therapy. Although microRNAs have been linked to GLP-1 signaling, their role in GLP-1RA monotherapy and combination therapy remains unclear. This review synthesizes current evidence of GLP-1RA-induced exosomal and non-exosomal miRNA changes in human and animal models of T2DM.

Methods

Scopus, PubMed/Medline, Web of Science, and Google Scholar searches returned 83 studies, of which 11 met the study eligibility criteria (PROSPERO No: CRD42024586000).

Results

Human studies showed GLP-1RA combined with metformin modulated non-exosomal miR-27b, miR-130a, and miR-210a, which were linked to cardiovascular health. In T2DM patients on metformin, higher baseline miR-378-3p or miR-126-3p correlated with greater HbA1c improvement after one year of GLP-1RA therapy. Notably, > 5% weight loss correlated with higher baseline levels of miR-15a-5p. Preclinical findings suggested GLP-1RA monotherapy increased cardiovascular action via non-exosomal miR-29b-3p, miR-34a-5p, miR-26a-5p, miR-181a-5p, and miR-93-5p. Silencing non-exosomal miR-204, miR-375, or miR-139-5p augmented exendin-4/liraglutide monotherapy-induced glucose-stimulated insulin secretion. Interestingly, GLP-1RA monotherapy reduced hepatic lipid accumulation in T2DM models with comorbid NAFLD via ABHD6 mRNA modulation by non-exosomal miR-5120. No clinical studies reported exosomal miRNAs, but a preclinical study linked GLP-1RA-induced exosomal let-7c-2-3p/miR-322-3p to bone protection in estrogen-deficient T2DM models.

Conclusion

GLP-1RAs, both as first-line and second-line therapies, are beneficial for T2DM complicated by obesity, NAFLD, cardio-metabolic disease, and postmenopausal osteoporosis. Longitudinal trials that incorporate innovative multi-omics approaches are essential for distinguishing their miRNA expression pattern from other anti-diabetics.