Yu Haifeng, Davoudi Maryam, Sadegh-Nejadi Sahar, Miao Xiaolei, Bagherieh Molood, Afrisham Reza
Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, Hubei Province, China.
Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
J Transl Med. 2025 Apr 25;23(1):477. doi: 10.1186/s12967-025-06461-y.
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.
Scopus, PubMed/Medline, Web of Science, and Google Scholar searches returned 83 studies, of which 11 met the study eligibility criteria (PROSPERO No: CRD42024586000).
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.
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.
胰高血糖素样肽-1受体激动剂（GLP-1RAs）是治疗2型糖尿病（T2DM）和肥胖症的有效疗法，尤其适用于对长期胰岛素治疗耐药的患者。尽管微小RNA与GLP-1信号传导有关，但其在GLP-1RA单药治疗和联合治疗中的作用仍不清楚。本综述综合了T2DM人类和动物模型中GLP-1RA诱导的外泌体和非外泌体微小RNA变化的现有证据。
通过Scopus、PubMed/Medline、Web of Science和Google Scholar检索，共检索到83项研究，其中11项符合研究纳入标准（PROSPERO编号：CRD42024586000）。
人体研究表明，GLP-1RA联合二甲双胍可调节与心血管健康相关的非外泌体miR-27b、miR-130a和miR-210a。在接受二甲双胍治疗的T2DM患者中，较高的基线miR-378-3p或miR-126-3p与GLP-1RA治疗一年后糖化血红蛋白（HbA1c）的更大改善相关。值得注意的是，体重减轻>5%与较高的基线miR-15a-5p水平相关。临床前研究结果表明，GLP-1RA单药治疗通过非外泌体miR-29b-3p、miR-34a-5p、miR-26a-5p、miR-181a-5p和miR-93-5p增强心血管作用。沉默非外泌体miR-204、miR-375或miR-139-5p可增强艾塞那肽/利拉鲁肽单药治疗诱导的葡萄糖刺激的胰岛素分泌。有趣的是，GLP-1RA单药治疗通过非外泌体miR-5120对ABHD6 mRNA的调节，减少了合并非酒精性脂肪性肝病（NAFLD）的T2DM模型中的肝脏脂质积累。尚无临床研究报道外泌体微小RNA，但一项临床前研究将GLP-1RA诱导的外泌体let-7c-2-3p/miR-322-3p与雌激素缺乏的T2DM模型中的骨保护联系起来。
GLP-1RAs作为一线和二线治疗药物，对合并肥胖、NAFLD、心脏代谢疾病和绝经后骨质疏松症的T2DM有益。纳入创新多组学方法的纵向试验对于区分其微小RNA表达模式与其他抗糖尿病药物至关重要。
