Li Huaping, Yang Hao, Liu Jingyan, Yang Hedi, Gao Xinyu, Yang Xiaoying, Liu Zhou, Qian Qiaohui
Department of Obstetrics and Gynecology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China.
Shanghai Key Laboratory of Molecular Imaging, Jiading District Central Hospital Affiliated Shanghai University of Medicine and Health Sciences, Shanghai, China.
Diabetol Metab Syndr. 2024 May 19;16(1):105. doi: 10.1186/s13098-024-01276-1.
Gestational diabetes mellitus (GDM) is a highly prevalent disease and poses a significant risk to the health of pregnant women. Abdominal adipose tissue (AT) contributes to insulin resistance (IR) associated with GDM. However, the underlying mechanisms remain unclear.
In this study, we developed a mouse model of GDM by subjecting mice to a high-fat diet. We collected adipose-derived stem cells (ADSCs) from the abdominal and inguinal regions and examined their role in inducing IR in normal tissues through the secretion of small extracellular vesicles (sEVs). The sEVs derived from ADSCs isolated from GDM mice (ADSC/GDM) were found to inhibit cell viability and insulin sensitivity in AML12, a normal mouse liver cell line.
Through proteomic analysis, we identified high levels of the thrombospondin 1 (Thbs1) protein in the sEVs derived from ADSC/GDM. Subsequent overexpression of Thbs1 protein in AML12 cells demonstrated similar IR as observed with ADSC/GDM-derived sEVs. Mechanistically, the Thbs1 protein within the sEVs interacted with CD36 and transforming growth factor (Tgf) β receptors in AML12 cells, leading to the activation of Tgfβ/Smad2 signaling. Furthermore, the administration of LSKL, an antagonistic peptide targeting Thbs1, suppressed Thbs1 expression in ADSC/GDM-derived sEVs, thereby restoring insulin sensitivity in AML12 cells and GDM mice in vivo.
These findings shed light on the intercellular transmission mechanism through which ADSCs influence hepatic insulin sensitivity and underscore the therapeutic potential of targeting the Thbs1 protein within sEVs.
妊娠期糖尿病（GDM）是一种高度流行的疾病，对孕妇的健康构成重大风险。腹部脂肪组织（AT）导致与GDM相关的胰岛素抵抗（IR）。然而，其潜在机制仍不清楚。
在本研究中，我们通过给小鼠喂食高脂饮食建立了GDM小鼠模型。我们从腹部和腹股沟区域收集脂肪来源干细胞（ADSCs），并通过分泌小细胞外囊泡（sEVs）研究它们在正常组织中诱导IR的作用。发现从GDM小鼠分离的ADSCs（ADSC/GDM）来源的sEVs抑制正常小鼠肝细胞系AML12中的细胞活力和胰岛素敏感性。
通过蛋白质组学分析，我们在ADSC/GDM来源 的sEVs中鉴定出高水平的血小板反应蛋白1（Thbs1）蛋白。随后在AML12细胞中过表达Thbs1蛋白显示出与ADSC/GDM来源的sEVs相似的IR。机制上，sEVs中的Thbs1蛋白与AML12细胞中的CD36和转化生长因子（Tgf）β受体相互作用，导致Tgfβ/Smad2信号通路激活。此外，给予靶向Thbs1的拮抗肽LSKL可抑制ADSC/GDM来源的sEVs中Thbs1的表达，从而恢复AML12细胞和体内GDM小鼠的胰岛素敏感性。
这些发现揭示了ADSCs影响肝脏胰岛素敏感性的细胞间传递机制，并强调了靶向sEVs中Thbs1蛋白的治疗潜力。
