Department of Molecular Medicine & Biotechnology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, 226014, India.
Institute of Molecular Medicine - Jamia Hamdard, Hamdard Nagar, New Delhi, Delhi, 110062, India.
Sci Rep. 2020 Jun 4;10(1):9102. doi: 10.1038/s41598-020-65970-6.
We determined the role of cellular fibronectin (CFN) containing the alternatively spliced extra domain A (FN-EDA) in causing insulin resistance (IR) through toll-like receptor 4 (TLR4). Circulating FN-EDA level was evaluated in mouse and rat IR models. Specific anti-FN-EDA antibody and TLR4 inhibitor were used to study its role in IR in mice. CFN protein was injected to evaluate TLR4 dependent effect of FN-EDA in IR. Furthermore, FN-EDA was estimated in blood plasma and correlated with demographic and clinical characteristics in healthy human participants (n = 38). High-fat diet feeding significantly increased circulating FN-EDA in both mouse (P = 0.03) and rat (P = 0.02) IR models. Antibody against FN-EDA protected mice from IR by increasing glucose disposal rate following glucose (P = 0.02) and insulin (P = 0.01) tolerance tests. CFN protein injection caused IR, however, TLR4 inhibitor protected the mice from CFN induced IR. Multivariate regression analysis predicted an independent positive correlation between circulating FN-EDA and fasting plasma glucose (P = 0.003) in healthy human participants. In conclusion, FN-EDA may cause IR through TLR4 by decreasing glucose disposal rate following glucose and insulin load. Targeting FN-EDA thus can be considered as a possible therapeutic strategy to delay prediabetes progression to diabetes.
我们通过 Toll 样受体 4（TLR4）确定了含有交替剪接外显子 A（FN-EDA）的细胞纤维连接蛋白（CFN）在导致胰岛素抵抗（IR）中的作用。评估了小鼠和大鼠 IR 模型中的循环 FN-EDA 水平。使用特异性抗 FN-EDA 抗体和 TLR4 抑制剂来研究其在小鼠 IR 中的作用。注射 CFN 蛋白以评估 FN-EDA 在 IR 中对 TLR4 的依赖性作用。此外，在健康人类参与者（n=38）中估计了 FN-EDA 在血浆中的含量，并将其与人口统计学和临床特征相关联。高脂饮食喂养在小鼠（P=0.03）和大鼠（P=0.02）IR 模型中均显著增加了循环 FN-EDA。针对 FN-EDA 的抗体通过增加葡萄糖处置率来保护小鼠免受 IR，在葡萄糖（P=0.02）和胰岛素（P=0.01）耐量试验后。CFN 蛋白注射会引起 IR，但是 TLR4 抑制剂可保护小鼠免受 CFN 引起的 IR。多元回归分析预测在健康人类参与者中，循环 FN-EDA 与空腹血浆葡萄糖之间存在独立的正相关（P=0.003）。总之，FN-EDA 可能通过降低葡萄糖和胰岛素负荷后的葡萄糖处置率，通过 TLR4 引起 IR。因此，靶向 FN-EDA 可以被认为是一种延迟糖尿病前期进展为糖尿病的可能治疗策略。
