Mesenchymal stem cell (MSC)-based therapy is currently considered to be an effective treatment strategy for diabetes and hepatic disorders, such as liver cirrhosis and non-alcoholic fatty liver disease. Exosomes are important mediators of cellular connections, and increasing evidence has suggested that exosomes derived from MSCs may be used as direct therapeutic agents; their mechanisms of action, however, remain largely unclear. Here, we evaluated the efficacy and molecular mechanisms of human umbilical cord MSC-derived exosomes (HucMDEs) on hepatic glucose and lipid metabolism in type 2 diabetes mellitus (T2DM). HucMDEs were used to treat T2DM rats, as well as palmitic acid (PA)-treated L-O2 cells, in order to determine the effects of HucMDEs on hepatic glucose and lipid metabolism. To evaluate the changes in autophagy and potential signaling pathways, autophagy-related proteins (BECN1, microtubule-associated protein 1 light chain 3 beta [MAP 1LC3B]), autophagy-related genes (ATGs, ATG5, and ATG7), AMP-activated protein kinase (AMPK), and phosphorylated AMPK (p-AMPK) were assessed by Western blotting. HucMDEs promoted hepatic glycolysis, glycogen storage, and lipolysis, and reduced gluconeogenesis. Additionally, autophagy potentially contributed to the effects of HucMDE treatment. Transmission electron microscopy revealed an increased formation of autophagosomes in HucMDE-treated groups, and the autophagy marker proteins, BECN1 and MAP 1LC3B, were also increased. Moreover, autophagy inhibitor 3-methyladenine significantly reduced the effects of HucMDEs on glucose and lipid metabolism in T2DM rats. Based on its phosphorylation status, we found that the AMPK signaling pathway was activated and induced autophagy in T2DM rats and PA-treated L-O2 cells. Meanwhile, the transfection of AMPK siRNA or application of the AMPK inhibitor, Comp C, weakened the therapeutic effects of HucMDEs on glucose and lipid metabolism. These findings demonstrate that HucMDEs improved hepatic glucose and lipid metabolism in T2DM rats by activating autophagy via the AMPK pathway, which provides novel evidence suggesting the potential for HucMDEs in clinically treating T2DM patients.

中文翻译：

---

间充质干细胞来源的外泌体通过增强自噬改善肝脏糖脂代谢，从而在 2 型糖尿病中发挥改善作用。

基于间充质干细胞 (MSC) 的治疗目前被认为是治疗糖尿病和肝脏疾病（如肝硬化和非酒精性脂肪肝疾病）的有效治疗策略。外泌体是细胞连接的重要介质，越来越多的证据表明源自 MSCs 的外泌体可用作直接治疗剂；然而，它们的作用机制在很大程度上仍不清楚。在这里，我们评估了人脐带间充质干细胞衍生的外泌体 (HucMDE) 对 2 型糖尿病 (T2DM) 肝脏葡萄糖和脂质代谢的功效和分子机制。HucMDEs 用于治疗 T2DM 大鼠，以及棕榈酸 (PA) 处理的 L-O2 细胞，以确定 HucMDEs 对肝脏葡萄糖和脂质代谢的影响。为了评估自噬和潜在信号通路的变化，自噬相关蛋白（BECN1、微管相关蛋白 1 轻链 3 β [MAP 1LC3B]）、自噬相关基因（ATGs、ATG5 和 ATG7）、AMP 激活蛋白通过蛋白质印迹评估激酶 (AMPK) 和磷酸化 AMPK (p-AMPK)。HucMDEs 促进肝糖酵解、糖原储存和脂肪分解，并减少糖异生。此外，自噬可能有助于 HucMDE 治疗的效果。透射电子显微镜显示，HucMDE 处理组中自噬体的形成增加，自噬标记蛋白 BECN1 和 MAP 1LC3B 也增加。此外，自噬抑制剂 3-甲基腺嘌呤显着降低了 HucMDE 对 T2DM 大鼠糖脂代谢的影响。基于其磷酸化状态，我们发现 AMPK 信号通路在 T2DM 大鼠和 PA 处理的 L-O2 细胞中被激活并诱导自噬。同时，AMPK siRNA的转染或AMPK抑制剂Comp C的应用削弱了HucMDEs对糖脂代谢的治疗作用。这些发现表明，HucMDEs 通过 AMPK 通路激活自噬改善了 T2DM 大鼠的肝脏葡萄糖和脂质代谢，这提供了新的证据，表明 HucMDEs 在临床治疗 T2DM 患者中的潜力。