Inhibition of JAK-STAT and NF-κB signalling systems could be a novel therapeutic target against insulin resistance and type 2 diabetes
Inhibition of JAK-STAT and NF-κB signalling systems could be a novel therapeutic target against insulin resistance and type 2 diabetes
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DOI：
10.1016/j.lfs.2019.117045
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发表时间：
2019-12-15
期刊：
影响因子：
6.1
通讯作者：
Ibrahim, Sani
中科院分区：
文献类型：
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作者：
Bako, Hauwa'u Yakubu;Ibrahim, Mohammed Auwal;Ibrahim, Sani
目的：慢性炎症与通过JAK-STAT和NF-kappa B信号通路产生高水平的促炎细胞因子有关，而托法替尼和阿司匹林分别抑制这两种信号通路。这些细胞因子的高水平增加了细胞因子抑制物(SOCs)的合成，高水平的SOC抑制了导致胰岛素抵抗的胰岛素信号。观察托法替尼和阿司匹林对2型糖尿病大鼠胰岛素抵抗程度的影响。材料与方法：用10%果糖溶液(自由饮用)加注射链脲佐菌素(40 mg/kgbw)复制2型糖尿病大鼠模型，分别给予不同剂量的托法替尼(10 mg/kgbw)、阿司匹林(100 mg/kgbw)和阿司匹林(100 mg/kgbw)及两者合用治疗9周。主要研究结果：结果表明：托法替尼10 mg/kgbw和阿司匹林100 mg/kgbw单独给药治疗9周，差异有统计学意义(P<；与未治疗的糖尿病大鼠相比，肿瘤坏死因子-α、白细胞介素6和血清淀粉样蛋白A显著降低。联合治疗(10 mg/kgbw tofacitinib和100 mg/kgbw阿司匹林)可显著降低T2D大鼠血清中TNF-α、IL-6、血清淀粉样蛋白A、HOMA-IR、血糖水平和SOC-3基因表达，但显著改善血糖同质、胰岛素分泌、HOMA-β和GLUT-4基因表达(P<；0.05)。结论：分别应用托法替尼和阿司匹林同时抑制JAK-STAT和NF-kappaB信号通路，可缓解T2D大鼠胰岛素抵抗和高血糖。
Aims: Chronic inflammation is associated with the production of high levels of proinflammatory cytokines via the JAK-STAT and NF-kappa B signalling pathways which are known to be inhibited by tofacitinib and aspirin respectively. High levels of these cytokines increase the synthesis of suppressors of cytokines (SOCS), which at high levels inhibit insulin signalling leading to insulin resistance. The effects of tofacitinib and aspirin on the degree of insulin resistance in type 2 diabetic rats were determined.Materials and methods: Rats were induced with type 2 diabetes (T2D) by administration of 10% fructose solution (ad libitum) followed by streptozotocin injection (40 mg/kg BW) and treated with different doses of tofacitinib (10 and 20 mg/kg BW), aspirin (100 and 200 mg/kg BW) and combination of the two drugs at both doses for 9 weeks.Key findings: Results showed that separate treatment with 10 mg/kg BW tofacitinib and 100 mg/kg BW aspirin significantly (P < 0.05) decreased tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and serum amyloid A when compared to diabetic untreated rats. However, the combined therapy (10 mg/kg BW tofacitinib and 100 mg/kg BW aspirin) significantly decreased the levels of TNF-alpha, IL-6, serum amyloid A, HOMA-IR, blood glucose level and SOC-3 gene expression but significantly (P < 0.05) improved glucose homoestasis, insulin secretion, HOMA-beta and GLUT-4 gene expression when compared to diabetic untreated rat.Conclusion: It was concluded that simultaneous inhibition of the JAK-STAT and NF-kappa B signalling pathways with tofacitinib and aspirin respectively, could mitigate insulin resistance and hyperglycemia in T2D.