Lotusine (LT), a compound extracted from Nelumbo nucifera, is being studied as a potentially safer, natural therapeutic antioxidant alternative to chemical drugs for diabetes management. The present study aims to investigate LT's protective effects against D-glucose-induced oxidative stress in HepG2 cells, focusing on antioxidant enzyme activities and insulin signaling pathways. Administrating D-glucose (25 mM) to HepG2 cells increased MDA by 56%, indicative of heightened lipid peroxidation, which was significantly (P<0.05) reduced by LT, maintaining 90 % of the cell viability. D-glucose also considerably (P<0.05) decreased the activity of antioxidant enzymes, where the activity of SOD and CAT decreased by 2.2-fold after 48 hours, and GPx activity dropped by 38% after 48 h of treatment.  LT effectively reversed these reductions, boosting antioxidant enzyme activity. Furthermore, LT (200 µg/ml) reduced the activity of α-amylase and α-glucosidase by 80.36% and 82.6%, respectively, with IC50 of 30.60 µg/ml for α-amylase and 36.15 µg/ml for α-glucosidase, compared to acarbose and EGCG. Alongside the downregulating expression of IRS-1 and AKT-2, GLUT4 is upregulated. In silico docking studies highlighted LT's affinity for proteins involved in diabetes pathophysiology. The in vitro results indicated that LT might mitigate oxidative stress, enhance antioxidant defenses in hyperglycemia, and be a potential therapeutic agent against hepatic oxidative damage. The in vivo study involved four groups of ten rats each. Group 1 was the normal control, Group 2 was the streptozotocin-treated diabetic control, Group 3 received glibenclamide, and Group 4 received a lotus-supplemented diet. All groups were fed a normal control diet for four weeks. Diabetic rats exhibited lower BWG, FCR, and GR; dietary LT enhanced the growth parameters in G3 and G4. Also, the diabetic rats showed reduced serum, liver, and pancreatic vitamin C and E levels, which LT treatment effectively restored. LT significantly (P<0.05) increased liver cell protein content to 11.6 mg/g, with a relative increase of 21 % compared to glibenclamide-treated rats; however, diabetic rats showed a significant (P<0.05) decrease in protein content.

To Cite This Article: Alharthi NS, 2025. Prophylactic impacts of lotusine against hyperglycaemia-induced oxidative stress in hepatic cells isolated from diabetic rats via IRS-1/PI3 K/Akt pathway. Pak Vet J. http://dx.doi.org/10.29261/pakvetj/2025.123