Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, 44519, Egypt.
Eur J Pharmacol. 2020 Apr 5;872:172959. doi: 10.1016/j.ejphar.2020.172959. Epub 2020 Jan 29.
Infliximab (IFX), a monoclonal antibody for tumor necrosis factor-alpha (TNF-α), is known to restore blood glucose homeostasis. However, its effects on improving renal insulin resistance (IR) are not yet studied. So we investigate the impact of infliximab on renal insulin signaling pathway in IR rat model regarding to metformin (MET). The induced IR was confirmed by a high oral glucose tolerance test, an elevation of lipid profile and the homeostatic model assessment of insulin resistance 2 (HOMA-IR 2) values. Subsequently, IR rats were concurrently treated with either MET (100 mg/kg/day) or IFX (one dose 5 mg/kg) besides IR and normal control (NC) groups. Four weeks later, IR control rats displayed hyperglycemia, hyperinsulinemia and elevation in HOMA-IR 2, renal function markers and renal tissue TNF-α, interleukins-1β and 6 (Il-1β, IL-6) and suppressor of cytokines signaling 3 (SOCS3) contents as well as glomerulosclerosis when compared to NC group. Additionally, the phosphorylation of renal insulin receptor substrate 1 (IRS1), phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt) were markedly impaired. Treatment with either MET or IFX significantly improved IR and kidney functions. The effects of the drugs were achieved by the downregulation of renal inflammatory cytokines and SOCS3 levels and the amelioration of the renal IRS1/PI3K/Akt pathway. In conclusion, MET and IFX ameliorated the TNF-α worsening effect on IR in rat renal tissues by regulating insulin signaling. Interestingly, infliximab was superior to metformin in regulating insulin signaling pathway. Therefore, infliximab could be used as an adjuvant therapy in improving renal IR.
英夫利昔单抗（IFX）是一种针对肿瘤坏死因子-α（TNF-α）的单克隆抗体，已知可恢复血糖稳态。然而，其改善肾胰岛素抵抗（IR）的作用尚未得到研究。因此，我们研究了英夫利昔单抗对伴有二甲双胍（MET）的 IR 大鼠模型肾胰岛素信号通路的影响。通过高口服葡萄糖耐量试验、血脂谱升高和稳态模型评估的胰岛素抵抗 2（HOMA-IR 2）值证实了 IR 的诱导。随后，IR 大鼠同时接受 MET（100mg/kg/天）或 IFX（一次剂量 5mg/kg）治疗，除了 IR 和正常对照组（NC）。四周后，与 NC 组相比，IR 对照组大鼠出现高血糖、高胰岛素血症和 HOMA-IR 2 升高、肾功能标志物和肾组织 TNF-α、白细胞介素-1β和 6（IL-1β、IL-6）以及细胞因子信号转导抑制因子 3（SOCS3）含量升高以及肾小球硬化。此外，肾胰岛素受体底物 1（IRS1）、磷酸肌醇 3-激酶（PI3K）和蛋白激酶 B（Akt）的磷酸化明显受损。MET 或 IFX 的治疗显著改善了 IR 和肾功能。药物的作用是通过下调肾炎症细胞因子和 SOCS3 水平以及改善肾 IRS1/PI3K/Akt 途径来实现的。总之，MET 和 IFX 通过调节胰岛素信号改善了 TNF-α 对大鼠肾组织 IR 的恶化作用。有趣的是，英夫利昔单抗在调节胰岛素信号通路方面优于二甲双胍。因此，英夫利昔单抗可作为改善肾 IR 的辅助治疗。
