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目的:观察胰腺β细胞中电导钙激活钾离子通道(intermediate-conductance Ca~(2+) -activated K+channel,K_(Ca)3.1)在2型糖尿病发病中的作用及调节机制。方法:应用2型糖尿病小鼠(db/db)模型,测评阻断K_(Ca)3.1对2型糖尿病表型指标的影响。分离小鼠胰腺β细胞,观察分别阻断K_(Ca)3.1和NF-κB信号通路对高糖或软脂酸诱导的NF-κB下游炎性细胞因子释放的影响。结果:K_(Ca)3.1阻断剂TRAM-34可降低db/db小鼠随时血糖水平。连续用药8周后,TRAM-34可降低db/db小鼠空腹血糖,改善葡萄糖耐量,增加餐后胰岛素水平,减轻db/db小鼠胰腺炎症并延缓β细胞的消亡。但TRAM-34不影响正常饮食C57BL/6小鼠空腹血糖和餐后血糖水平,无低血糖副作用。在分离的小鼠胰腺β细胞,分别阻断K_(Ca)3.1和NF-κB可降低高糖或软脂酸所引起的炎性趋化因子(CCL2和CCL20)的释放。结论:NF-κB活化介导胰腺β细胞K_(Ca)3.1上调,协同调节炎性细胞因子和胰岛素分泌,促发胰岛炎症和β细胞功能障碍,导致2型糖尿病。
OBJECTIVE: To observe the role and regulation mechanism of Ca2 + -activated K + channel (K-Ca2 +) in pancreatic β cells in the pathogenesis of type 2 diabetes mellitus (T2DM). Methods: The model of type 2 diabetes mellitus (db / db) was used to evaluate the effect of blocking K (Ca) 3.1 on the phenotype of type 2 diabetes mellitus. The effects of K (Ca) 3.1 and NF-κB signaling pathway on the release of inflammatory cytokines downstream of NF-κB induced by high glucose or palmitate were respectively observed. Results: K (Ca) 3.1 blocker TRAM-34 decreased blood glucose level in db / db mice at any time. After continuous administration for 8 weeks, TRAM-34 could reduce fasting blood glucose, improve glucose tolerance, increase postprandial insulin level, alleviate pancreatic inflammation and delay β cell death in db / db mice. However, TRAM-34 did not affect the fasting blood glucose and postprandial blood glucose levels in normal diet C57BL / 6 mice without hypoglycemic side effects. In isolated mouse pancreatic β-cells, blocking K_ (Ca) 3.1 and NF-κB, respectively, decreased the release of inflammatory chemokines (CCL2 and CCL20) caused by high glucose or palmitate. CONCLUSION: NF-κB activation induces up-regulation of K_ (Ca) 3.1 in pancreatic β cells and synergistically regulates inflammatory cytokines and insulin secretion, promotes islet inflammation and β-cell dysfunction, leading to type 2 diabetes.