抑制LTB4/Ltb4r1相关炎症信号通路：小檗碱改善2型糖尿病胰岛素抵抗的分子机制？

Insulin resistance (IR) attributed to chronic low grade inflammatory response plays a key role in the development of type 2 diabetes mellitus (T2DM). Recent study showed that the inhibition of LTB4/ Ltb4r1 axis could improve insulin resistance. Berberine is the main ingredient of Chinese herb Coptis Chinensis, and showed anti-inflammatory, lipid lowering and hypoglycemic effects. However, the mechanism of it’s hypoglycemic effect is not yet fully elucidated. Based on the anti-inflammatory and insulin sensitization effect of berberine in our previous research, we hypothesize that berberine would alleviate IR in T2DM through the inhibition of LTB4/ Ltb4r1 related anti-inflammatory pathway. To test our hypothesis, a T2DM mice model will be established by high-glucose and high fat-diet feeding. Experiment has been designed to detect inflammatory cell chemotaxis and it’s inflammatory response, as well as the expression of LTB4/Ltb4r1. Moreover, the moleculer mechanism of inflammatory signaling and insulin conduction signaling will be detected in insulin sensitive cells both in vivo and in vitro. Different experimental techniques including molecular biology, biochemistry and immunology will be used. We believe that the successful completion of the proposed research will illustrate whether berberine improve IR by inhibiting LTB4/Ltb4r1 related inflammatory pathway in obesity related T2DM, based on which we will be able to provide a more adequate foundation for antidiabetic effect of berberine.

慢性低度炎症反应导致的胰岛素抵抗是2型糖尿病发生发展的重要原因。最新研究发现抑制LTB4/Ltb4r1炎症信号通路可以改善胰岛素抵抗。小檗碱是具有清热解毒功效的中药黄连的主要有效成分，具有抗炎、调脂、降糖等多重功效，其抗糖尿病作用得到广泛认同，然而机制却尚未阐明。本研究在前期发现小檗碱具有抗炎和改善T2DM胰岛素抵抗的基础上，提出“小檗碱可能通过抑制LTB4/Ltb4r1相关炎症信号通路改善T2DM胰岛素抵抗”这一假说。通过构建高糖高脂诱导的T2DM胰岛素抵抗小鼠模型，运用现代分子生物学、生物化学、分子免疫学等技术手段，结合离体实验研究，探讨小檗碱对炎性细胞趋化及其炎症反应、LTB4/Ltb4r1的表达、胰岛素敏感细胞炎症信号通路及胰岛素信号转导通路蛋白表达的影响，初步阐明小檗碱是否通过抑制LTB4/Ltb4r1相关炎症信号通路改善T2DM胰岛素抵抗，为小檗碱防治糖尿病提供更充分的依据。

慢性低度炎症反应导致的胰岛素抵抗是2型糖尿病发生发展的重要原因最新研究发现抑制LTB4/Ltb4r1炎症信号通路可以改善胰岛素抵抗。小檗碱是具有清热解毒功效的中药黄连的主要有效成分，具有抗炎、调脂、降糖等多重功效，其抗糖尿病作用得到广泛认同，然而机制却尚未阐明。项目提出“小檗碱可能通过抑LTB4/Ltb4r1相关炎症信号通路改善T2DM胰岛素抵抗”这一假说。本项目主要研究小檗碱改善db/db糖尿病小鼠胰岛素抵抗与抑制LTB4/Ltb4r1信号通路的关系，小檗碱通过LTB4/Ltb4r1信号通路对巨噬细胞趋化、炎症反应及HepG2细胞胰岛素抵抗的影响。研究发现小檗碱显著降低血清、肝脏、脂肪组织的炎症因子表达，改善糖尿病小鼠的空腹血糖及胰岛素抵抗，且抑制LTB4的表达；小檗碱促进LTB4诱导的HepG2细胞的葡萄糖摄取，促进胰岛素信号通路关键蛋白p-AKT、GLUT4的表达，降低HepG2细胞炎症因子IL-6、TNF-α mRNA表达水平；小檗碱抑制LTB4诱导的RAW264.7的胞内炎症信号蛋白表达。这些结果表明，小檗碱改善胰岛素抵抗与其抗炎作用相关，而LTB4/Ltb4r1信号通路是其可能的抗炎信号通路。该研究成果为小檗碱治疗代谢性疾病提供了科学依据。