补钾通过调节慢性炎症环境改善高盐诱导的胰岛素抵抗的机制研究

Substantial evidence show that high dietary salt intake is positively associated with autoimmune and inflammatory diseases such as metabolic syndrome，characterized by insulin resistance，whereas high potassium intake, particularly in subjects with high salt intake, is inversely related with these disorders. Inflammation，marked by the production and excretion of cytokines, plays an critical role in development of these diseases. Notwithstanding, the exact molecular mechanisms involved are still poorly understood. Data from our laboratory have previously revealed that high salt diet might render plasma IL-1β，IL-17A productions increment，whereas potassium supplementation could reverse the effects. The amelioration caused by potassium supplementation in high-salt-induced HOMA-IR（the evaluation index of insulin resistance） in participants may be related to the decrease of the two cytokines. Its relevant molecular mechanisms involved in NLRP3 inflammasome and p38/MAPK-SGK1 signal pathway. These findings arouse our great interest in exploring further in this field. Therefore, this study was designed to probe the impact of high salt intake and potassium supplementation on other cytokines such as IL-6 IL-12，IL-21，IL-23，TGF-β，TNF-α，IFN-γ etc. productions in monocytes/ macrophages and T lymphocytes，and the correlations with HOMA-IR, meanwhile, the exact molecular mechanisms revealing that the polarizations of macrophages and T lymphocytes，and the productions of cytokines modulated by high salt and potassium supplementation.

高盐摄入促进胰岛素抵抗的发生，而钾的补充可显著改善胰岛素抵抗。机体慢性、持续、低强度的炎症环境是胰岛素抵抗的重要特征，多种免疫细胞及炎性/抑炎细胞因子参与了疾病过程。我们在前期研究中发现，高盐饮食显著升高受试者血浆炎性细胞因子IL-1β、IL-17A的表达，且这一现象与胰岛素抵抗的发生正相关；而钾的补充可逆转IL-1β、IL-17A表达的上调，其机制与NLRP3炎性小体、p38/MAPK-SGK1信号通路有关；这引起了我们的兴趣，高盐及补钾对其它炎性/抑炎细胞因子表达的调节及具体分子机制仍有待进一步挖掘。因此，本课题拟利用人群饮食干预及细胞分子生物学实验，从体内、体外探讨：1）高盐摄入及补钾对受试者慢性炎症环境的影响，及与胰岛素抵抗的相关性；2）高盐干预及补钾对巨噬细胞M1/M2分型、T淋巴细胞极化及炎性/抑炎细胞因子表达的影响及可能涉及的信号通路。

机体慢性、持续、低强度的炎症环境是胰岛素抵抗的重要特征，多种免疫细胞及炎性/抑炎细胞因子参与了疾病过程。我们在前期研究中发现，高盐饮食显著升高受试者血浆炎性细胞因子IL-1 β、IL-17A的表达，且这一现象与胰岛素抵抗的发生正相关；而钾的补充可逆转IL-1β、IL-17A表达的上调，其机制与NLRP3炎性小体、p38/MAPK-SGK1信号通路有关。本课题利用人群饮食干预及细胞分子生物学实验，从体内、体外探讨高盐摄入及补钾对受试者慢性炎症环境的影响，及与胰岛素抵抗的相关性；并探索高盐干预及补钾对T淋巴细胞极化及炎性/抑炎细胞因子表达的影响及可能涉及的信号通路。结果显示，补钾可以逆转高盐负荷导致的受试者胰岛素抵抗指数HOMA-IR的升高，高盐不但可通过激活p38/MAPK-SGK1信号通路促进淋巴细胞IL-17A高表达，还可通过上调TGF-β及IL-6等炎性因子的分泌促进淋巴细胞Th17转录因子RORα及RORγt的表达，从而诱导IL-17A产生，进而促进细胞向Th17分化，而补钾则可抑制高盐的这些作用。本课题探索出，高盐饮食能通过促进循环中炎性细胞因子的表达而导致高血压、胰岛素抵抗等免疫炎症性疾病的发生及进展，而钾的补充可能对这一致病过程具有逆转作用，对人群健康具有指导意义。