Miao Xiaolei, Davoudi Maryam, Alitotonchi Zahra, Ahmadi Ensieh Sadat, Amraee Fatemeh, Alemi Ashraf, Afrisham Reza
School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, 437100, China.
Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran.
Diabetol Metab Syndr. 2025 Jan 10;17(1):13. doi: 10.1186/s13098-025-01581-3.
Type 2 diabetes mellitus (T2DM) is usually complicated by cardiovascular diseases, hyperglycemia, and obesity, which worsen the outcome for the patient. Since recent evidence underlines the epigenetic role of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in the management of these comorbidities, this study compared the effects of these agents, namely liraglutide, semaglutide, dulaglutide, and exenatide, on miRNA regulation in the management of T2DM.
GLP-1RAs modify the expression of miRNAs involved in endothelial function, sugar metabolism, and adipogenesis, including but not limited to miR-27b, miR-130a, and miR-210. Baseline miR-15a-5p predict weight loss, while higher miR-378-3p and miR-126-3p levels are related to better glycemic control and lower HbA1c and FPG at one year post-treatment. miR-375-5p was also reported as a predictor of HbA1c levels. Liraglutide has a protecting effect against pancreatic β-cell apoptosis by downregulating miR-139-5p. The highly-expressed miR-375 in pancreatic islets can be considered as a biomarker for assessing the cytoprotective action of GLP-1RAs on β-cells. GLP-1RAs also enhance β-cell responsiveness by promoting GLP-1 receptor expression through the suppression of miR-204. While semaglutide, semaglutide, and dulaglutide reduce both systolic and diastolic blood pressures, lixisenatide and exenatide QW did not reveal such an effect. The long-acting exenatide-induced miR-29b-3p is required for the protection against diabetic cardiomyopathy. Liraglutide modulates critical regulators of endothelial cell function and atherosclerosis, including miR-93-5p, miR-26a-5p, and miR-181a-5p. Eventually, GLP-1RAs regulation of exosomal miRNAs, such as miR-192, implicated in the development of fibrosis and inflammation in T2DM micro-cardiovascular outcomes like DKD and DR.
Additional studies will be needed in the elucidation of the relations between GLP-1RA-induced miRNAs and clinical-laboratory findings concerning the diverse populations, gender, and presence of other comorbid states in treated patients with T2DM.
2型糖尿病（T2DM）通常并发心血管疾病、高血糖和肥胖，这些会使患者的病情恶化。由于近期证据强调了胰高血糖素样肽-1受体激动剂（GLP-1RAs）在这些合并症管理中的表观遗传作用，本研究比较了这些药物，即利拉鲁肽、司美格鲁肽、度拉鲁肽和艾塞那肽，在T2DM管理中对miRNA调控的影响。
GLP-1RAs可改变参与内皮功能、糖代谢和脂肪生成的miRNA的表达，包括但不限于miR-27b、miR-130a和miR-210。基线miR-15a-5p可预测体重减轻，而较高的miR-378-3p和miR-126-3p水平与治疗后一年更好的血糖控制以及更低的糖化血红蛋白（HbA1c）和空腹血糖（FPG）相关。miR-375-5p也被报道为HbA1c水平的预测指标。利拉鲁肽通过下调miR-139-5p对胰腺β细胞凋亡具有保护作用。胰岛中高表达的miR-375可被视为评估GLP-1RAs对β细胞细胞保护作用的生物标志物。GLP-1RAs还通过抑制miR-204促进GLP-1受体表达来增强β细胞反应性。虽然司美格鲁肽、度拉鲁肽可降低收缩压和舒张压，但利司那肽和每周一次的艾塞那肽未显示出这种效果。长效艾塞那肽诱导的miR-29b-3p是预防糖尿病性心肌病所必需的。利拉鲁肽调节内皮细胞功能和动脉粥样硬化的关键调节因子，包括miR-93-5p、miR-26a-5p和miR-181a-5p。最终，GLP-1RAs对外泌体miRNA的调控，如miR-192，与T2DM微血管结局（如糖尿病肾病和糖尿病视网膜病变）中的纤维化和炎症发展有关。
需要进一步研究阐明GLP-1RA诱导的miRNA与T2DM治疗患者的不同人群、性别及其他合并症存在情况的临床实验室检查结果之间的关系。
