外泌体miR-27a-3p抑制SERT诱导围绝经期肝脏胰岛素抵抗的机制研究

围绝经期综合症人群易患糖尿病；流行病学数据揭示，潮红和盗汗等围绝经期综合征血管舒缩症状（VMS）与2型糖尿病患病率升高独立相关。新近研究提示，外周循环5-羟色胺（5-HT）可导致肝糖异生增加、血糖升高；而肝脏5-HT转运体（SERT）下调是关键因素。我们前期研究发现，围绝经期模型小鼠血清miR-27a-3p水平增高，生物数据库检索显示miR-27a-3p以外泌体为载体，并与SERT基因存在结合位点，提示外泌体miR-27a-3p具有抑制SERT表达的潜在作用；但对其如何影响肝糖代谢尚不明确。本研究将从体内和体外实验探讨围绝经期外泌体miR-27a-3p的来源和转运途径，及其对肝脏5-HT系统和胰岛素信号转导通路的影响，明确其在肝脏胰岛素抵抗形成过程中的作用，阐明围绝经期VMS人群糖尿病风险增高的机制，为防治围绝经期女性糖尿病提供新的思路和干预靶点。

Women with perimenopausal syndrome are prone to develop diabetes mellitus. Recent epidemiology study showed vasomotor symptoms (VMS) of perimenopausal syndrome such as hot flush and night sweat, were independently associated with type 2 diabetes mellitus. It was reported lately that peripheral 5-HT plays an important role in hepatic glucose metabolism, in which, serotonin transporter (SERT) down-regulation may be a key factor. Our previous work indicated that serum miR-27a-3p was elevated in perimenopausal model mice. Prediction using TargetScan showed that miR-27a-3p have binding site in SERT mRNA and data of Vesiclepedia comfirmed that miR-27a-3p are transported by exosomes in circulation, suggesting that exosomal miR-27a-3p may inhibit SERT expression. However, the influence of miR-27a-3p on hepatic glucose metabolism remains unclear. This study is aimed to discuss the source and transport pathway of exosomal miR-27a-3p in perimenopause, and its role in hepatic 5-HT metabolism and insulin signal transduction. We expect to illuminate the effect of exosomal miR-27a-3p in hepatic insulin resistance and clarify the cause of increased incidence of T2DM in VMS population, in order to provide new method and intervention target in the prevention of T2DM in perimenopausal women.