Pharmaceutics &Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
Pharmaceutics &Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow 226031, India.
Life Sci. 2022 Jan 15;289:120221. doi: 10.1016/j.lfs.2021.120221. Epub 2021 Dec 10.
Free fatty acid-mediated obesity plays a crucial role in the pathogenesis of Type 2 Diabetes. FFA induced JNK activation acts as a central regulator in causing hepatic insulin resistance. Similarly, Pancreastatin, a chromogranin A peptide, serves as a crucial link between FFA-induced insulin resistance. Therefore, in the present work, we sought to test Pancreastatin inhibitor PSTi8 to ameliorate FFA-induced hepatic insulin resistance in in vitro and in vivo models.
To verify our objective, we exposed hepatocytes (HepG2 cells) with palmitate (0.3 mM) or palmitate + PSTi8 (200 nM). Parallelly mice were fed either HFD or HFD + PSTi8 (1 mg/kg). After 21 days animals were scanned for increased fat mass, along with GTT, ITT and PTT experiment to check glucose, and insulin tolerance. Furthermore, ROS generation and hepatic glycogen content was measured in FFA exposed hepatocytes. Gene expression and protein expression studies were further conducted to delineate the action mechanism of PSTi8.
PSTi8 exposure decreased ROS accumulation, lipid accumulation, and reduced glycogen content in FFA-induced groups. It also enhances glucose uptake and reduces gluconeogenesis to combat the FFA effect. Furthermore, gene expression studies indicate that PSTi8 treatment reduces NADPH oxidase3 (NOX3) expression and inhibits JNK signaling, a predominant source of ROS-induced insulin resistance.
To summarize, the protective effect of PSTi8 on FFA-induced insulin resistance is mediated via inhibition of JNK signaling, which leads to decreased ROS generation and enhanced insulin sensitivity. Hence PSTi8 could be a therapeutic molecule to prevent western diet-induced insulin resistance.
游离脂肪酸介导的肥胖在 2 型糖尿病的发病机制中起着关键作用。FFA 诱导的 JNK 激活作为导致肝胰岛素抵抗的中央调节剂。同样，胰淀素，一种嗜铬粒蛋白 A 肽，作为 FFA 诱导的胰岛素抵抗的关键环节。因此，在本工作中，我们试图测试胰淀素抑制剂 PSTi8 以改善体外和体内模型中的 FFA 诱导的肝胰岛素抵抗。
为了验证我们的目的，我们用棕榈酸（0.3 mM）或棕榈酸+ PSTi8（200 nM）暴露肝细胞（HepG2 细胞）。同时，将小鼠喂饲 HFD 或 HFD+PSTi8（1 mg/kg）。21 天后，对动物进行扫描以增加脂肪量，同时进行 GTT、ITT 和 PTT 实验以检查葡萄糖和胰岛素耐量。此外，在 FFA 暴露的肝细胞中测量 ROS 生成和肝糖原含量。进一步进行基因表达和蛋白质表达研究，以阐明 PSTi8 的作用机制。
PSTi8 暴露降低了 ROS 积累、脂质积累和 FFA 诱导组中的糖原含量。它还增强了葡萄糖摄取并减少了糖异生以抵抗 FFA 的作用。此外，基因表达研究表明，PSTi8 处理降低了 NADPH 氧化酶 3（NOX3）的表达并抑制了 JNK 信号通路，这是 ROS 诱导的胰岛素抵抗的主要来源。
总之，PSTi8 对 FFA 诱导的胰岛素抵抗的保护作用是通过抑制 JNK 信号通路介导的，这导致 ROS 生成减少和胰岛素敏感性增强。因此，PSTi8 可能是预防西方饮食诱导的胰岛素抵抗的治疗分子。
