Yang Sijue, Yuan Yue, Zhang Bing, Wu Tianyu, Yu Congcong, Li Fangyi, Zhu Wenhui, Zhai Beibei, Zhang Wen, Wang Jin, Zhang Zhou, Bi Yan
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
Branch of National Clinical Research Centre for Metabolic Diseases, Nanjing, China.
Diabetes Obes Metab. 2025 Mar;27(3):1265-1275. doi: 10.1111/dom.16121. Epub 2024 Dec 17.
To explore serum exosomal microRNAs (miRNAs) as risk biomarkers for early detection of cognitive impairment in type 2 diabetes mellitus (T2DM) patients.
This study included two phases: a discovery phase and a validation phase. To detect adipose tissue exosomal biomarkers for T2DM patients, small RNA sequencing was conducted on a discovery population consisting of six T2DM patients and five subjects with normal glucose tolerance. To identify miRNAs with causal effects on cognitive impairment, Mendelian randomization (MR) analysis using publicly available genome wide association studies (GWAS) datasets was performed. Relationships between serum exosomal miRNAs and cognitive impairment were evaluated in a training population of 207 T2DM patients, and further validated in an external population of 101 T2DM patients from multiple centres.
In the discovery phase, 13 exosomal miRNAs were significantly upregulated in adipose tissue of T2DM patients. MR analyses identified that increased miR-125a-5p was causally associated with increased Alzheimer's disease (AD) risk (OR = 1.231, 95% CI 1.062-1.426). In the validation phase, higher serum exosomal miR-125a-5p levels were related to increased amnestic mild cognitive impairment (aMCI) risk (OR = 1.066, 95% CI 1.030-1.103) and reduced left hippocampal body volume (r = -0.189, p < 0.05), achieving an area under the curve (AUC) of 0.728 for identifying aMCI in T2DM patients. External validation confirmed a diagnostic AUC of 0.738.
Serum exosomal miR-125a-5p derived from adipose tissue can serve as a causal biomarker for cognitive impairment in T2DM patients.
探讨血清外泌体微小核糖核酸（miRNA）作为2型糖尿病（T2DM）患者认知功能障碍早期检测的风险生物标志物。
本研究包括两个阶段：发现阶段和验证阶段。为了检测T2DM患者的脂肪组织外泌体生物标志物，对由6名T2DM患者和5名糖耐量正常的受试者组成的发现人群进行了小RNA测序。为了鉴定对认知功能障碍有因果影响的miRNA，使用公开可用的全基因组关联研究（GWAS）数据集进行了孟德尔随机化（MR）分析。在207名T2DM患者的训练人群中评估了血清外泌体miRNA与认知功能障碍之间的关系，并在来自多个中心的101名T2DM患者的外部人群中进行了进一步验证。
在发现阶段，13种外泌体miRNA在T2DM患者的脂肪组织中显著上调。MR分析确定，miR-125a-5p增加与阿尔茨海默病（AD）风险增加存在因果关系（比值比[OR]=1.231，95%置信区间[CI]1.062-1.426）。在验证阶段，较高的血清外泌体miR-125a-5p水平与遗忘型轻度认知障碍（aMCI）风险增加（OR=1.066，95%CI 1.030-1.103）和左侧海马体体积减小（r=-0.189，p<0.05）相关，在识别T2DM患者的aMCI方面曲线下面积（AUC）达到0.728。外部验证确认诊断AUC为0.738。
源自脂肪组织的血清外泌体miR-125a-5p可作为T2DM患者认知功能障碍的因果生物标志物。
