Diosgenin promoted glucose uptake by attenuation of high glucose induced blockade of PI3K-Akt-GLUT4 pathway and ER stress

Abstract

Introduction and Aim: Hyperglycemia is the signature style of type II diabetes (T2D) which impairs pathways of insulin signaling and endoplasmic reticulum (ER) stress. Diosgenin is a popular saponin known for its antidiabetic and anti-obesity properties predominantly found in Dioscorea species. However, the mechanism of hypoglycemic effects related to pathways of ER stress, insulin signaling, and uptake of glucose in the liver gained less attention. Accordingly, this study was aimed to assess the effect of Diosgenin on the uptake of glucose, insulin signaling as well as on ER stress in human HepG2 cells cultured in hyperglycemic or high glucose (HG) condition. Materials and Methods: Viability studies on HepG2 cells, assay for studying the uptake and consumption of glucose, gene expression, and docking studies were carried out. Results: The treatment with Diosgenin was found to elevate the uptake as well as consumption of glucose in HepG2 cells under hyperglycemic conditions. Diosgenin prevented inactivation of the PI3K Akt pathway as well as GLUT4 levels induced by high glucose. Furthermore, endoplasmic reticulum stress elements viz., inositol requiring enzyme 1 (IRE1), protein kinase like endoplasmic reticulum kinase (PERK), C/EBP homologous protein (CHOP) and sXBP1 were reduced by diosgenin treatment provoked by high glucose returning to normal ER homeostasis. Moreover, the effects are supported by the binding efficiency of diosgenin with insulin signaling proteins using bioinformatic tools. Conclusion: Our findings suggest that diosgenin elevated the uptake of glucose by hindering the inactivation of PI3K Akt GLUT4 pathway and ER stress caused by high glucose, thus, preventing further hepatic dysfunction.