Nomilin Ameliorates Insulin Resistance via Modulating the Glucose Metabolism and PI3K/Akt/GLUT4 signaling pathway in Type 2 Diabetes

Type 2 diabetes (T2D) became the most prevalent metabolic diseases worldwide characterized by insulin resistance (IR). Nomilin is a bioactive triterpene compound primarily found in citrus fruits and its anti-diabetes effect has been preliminary studied. This study combined network pharmacology, bioinformatics analysis and two insulin resistance cell models (HepG2 and THLE-2 cell line) were utilized to study the anti-diabetes effect of nomilin and its underlying molecular mechanisms. The network pharmacology and bioinformatics analysis showed that the PI3K/Akt signaling pathway is the critical signaling pathway to the anti-diabetes capability of nomilin. In both IR-HepG2 and IR-THLE-2 cell line, the nomilin can attenuate the high glucose and dexamethasone induced glucose consumption and uptake decrease, reactive oxygen species (ROS) and advanced glycation end-products (AGEs) generation, mitochondria pathological change, and mitochondria membrane potential loss. The Western Blot and In-cell Western results result showed that nomilin can achieve anti-diabetes effect through regulating the PI3K/Akt/GLUT4 signaling pathway and the phosphorylation of GSK3β. This study illustrated that nomilin alleviated insulin resistance via activation of PI3K/Akt/GLUT4 signaling pathways, alleviating ROS accumulation and damage, and AGEs production, and improving the mitochondrial function. Accordingly, nomilin shows potential as a promising bioactive component for nutritional intervention and management of hepatic insulin resistance.