Ethanolic Extract of Artemisia herba-alba Ameliorates Hyperinsulinemia and Hyperglycemia-Induced HepG2 Cells Through Cell Survival Promotion, Oxidative Stress Mitigation, and Insulin Signaling Restoration

Abstract

Background: In recent years, diabetes and its risk factors were linked to an augmented occurrence of cardiovascular diseases (CVD), which are considered major causes of morbidity and mortality in diabetes mellitus subjects. Hyperinsulinemia (HI) and hyperglycemia (HG) are recognized as insulin resistance-inducers, which can trigger several alterations in cellular biogenesis besides inflammatory signaling activation. As a folk medicine in many countries, Artemisia herbaalba has been preclinically studied for treatment of type 2 diabetes mellitus (T2DM) and showed beneficial effects on hyperglycemia. Methods: In the current work, we explored the potential mechanisms underlying the antihyperglycemic behavior of the ethanolic extract of A. herba-alba and its bioactive compounds. Results: Obtained data demonstrated that ethanolic extract of A. herba-alba enhances HepG2 viability and proliferation, decreases considerably the apoptosis, through the regulation of pro- and anti-apoptotic pathways implying p53, p21 and Bcl-2 genes expression and Pan caspases activation under IR concentration at the lowest concentrations. A. herba-alba extract treatment additionally exhibited a potential antioxidant effect, evidenced by the significant decrease in total intracellular reactive oxygen species (ROS) levels and the improved mitochondrial transmembrane potential in HG/HI-challenged HepG2 cells (p < 0.001). Furthermore, A. herba-alba positively upregulated Irs1 and Irs2 as well as Akt/Pi3K pathway compared to insulin-resistant untreated cells, and subsequently stimulated glucose uptake in response to insulin infusion, as a consequence of its signal transduction restoration. Conclusion: Overall, the obtained data highlighted the beneficial effects of A. herba-alba ethanolic extract in ameliorating insulin signaling and liver cells metabolic balance, and shed the light for its use as a promising and safe therapeutic lead for the management of type 2 diabetes and underlying metabolic failures.