Chen Huijian, Liu Pengxin, Pan Xin, Huang Mi, Li Tongqing, Guo Yan, Pang Zongran, Mohammadtursun Nabijan, Yang Xinzhou
International Cooperation Base for Active Substances in Traditional Chinese Medicine in Hubei Province, School of Pharmaceutical Sciences, South-Central Minzu University, Wuhan 430074, China.
School of Pharmacy, Minzu University of China, Beijing 100081, China.
Int J Biol Macromol. 2025 Apr;299:140048. doi: 10.1016/j.ijbiomac.2025.140048. Epub 2025 Jan 18.
Extracellular matrix (ECM) and integrins are important biological macromolecules. ECM especially collagen IV (COLIV) deposition modulates the integrin-FAK signaling pathway involved in adipogenesis and is strongly associated with insulin resistance. Type 2 diabetes mellitus (T2DM) mice were given swertiamarin (STM) by intragastric administration. STM reduced body weight, blood glucose, and lipid levels and enhanced insulin sensitivity in diabetic mice. The lipid accumulation in liver, gastrocnemius muscle, and inguinal subcutaneous white adipose tissue (igSWAT) were significantly reduced by STM. Bioinformatics analysis revealed a connection between ECM, ITGB1/FAK, and PI3K/Akt signaling pathways. STM downregulated the adipogenesis, IRβ expression, COLIV deposition, ITGB1/FAK, and PI3K/Akt signaling pathways in igSWAT of diabetic mice. In vitro, STM inhibited the glucose uptake and differentiation of adipocytes, and downregulated adipogenesis-related gene and protein expression. STM is bound to ITGB1 and downregulated COLIV deposition, ITGB1/FAK, and PI3K/Akt signaling pathways. When we overexpressed FAK, the effects of STM on downstream PI3K/Akt signaling pathway and adipogenesis were attenuated. In conclusion, STM reduced COLIV deposition and binding with ITGB1 to downregulate ITGB1/FAK signaling pathway, further the downstream PI3K/Akt signaling pathway was inhibited to reduce adipogenesis and ameliorated T2DM. Thus, these signals may be a novel mechanism of STM in treating T2DM.
细胞外基质（ECM）和整合素是重要的生物大分子。ECM尤其是IV型胶原（COLIV）的沉积调节参与脂肪生成的整合素-FAK信号通路，并且与胰岛素抵抗密切相关。对2型糖尿病（T2DM）小鼠进行獐牙菜苦苷（STM）灌胃给药。STM降低了糖尿病小鼠的体重、血糖和血脂水平，并增强了胰岛素敏感性。STM显著减少了肝脏、腓肠肌和腹股沟皮下白色脂肪组织（igSWAT）中的脂质积累。生物信息学分析揭示了ECM、ITGB1/FAK和PI3K/Akt信号通路之间的联系。STM下调了糖尿病小鼠igSWAT中的脂肪生成、IRβ表达、COLIV沉积、ITGB1/FAK和PI3K/Akt信号通路。在体外，STM抑制脂肪细胞的葡萄糖摄取和分化，并下调脂肪生成相关基因和蛋白的表达。STM与ITGB1结合并下调COLIV沉积、ITGB1/FAK和PI3K/Akt信号通路。当我们过表达FAK时，STM对下游PI3K/Akt信号通路和脂肪生成的作用减弱。总之，STM减少COLIV沉积并与ITGB1结合以下调ITGB1/FAK信号通路，进而抑制下游PI3K/Akt信号通路以减少脂肪生成并改善T2DM。因此，这些信号可能是STM治疗T2DM的新机制。
