ABSTRACT
BACKGROUND: Misfolded proteins accumulate in the liver due to endoplasmic reticulum stress (ERS) caused by high blood glucose levels in diabetes. This triggers the unfolded protein response (UPR), which if persistently activated, results in cellular dysfunction. Chronic ER stress increases inflammation, insulin resistance, and apoptosis. There is growing interest in using native plants and traditional medicine for diabetes treatment. The stevia plant has recently gained attention for its potential therapeutic effects. This study investigates the protective effects of aquatic stevia extract on liver damage, ER stress, and the UPR pathway in streptozotocin (STZ)-induced diabetic rats. METHODS: Rats were randomly divided into four groups: a control group that received 1 ml of water; a diabetic group induced by intraperitoneal injection of STZ (60 mg/kg); a diabetic group treated with metformin (500 mg/kg); and a diabetic group treated with aquatic extracts of stevia (400 mg/kg). After 28 days, various parameters were assessed, including inflammatory markers, oxidative stress indices, antioxidant levels, gene expression, stereology, and liver tissue pathology. RESULT: Compared to the diabetic control group, treatment with stevia significantly decreased serum glucose, liver enzymes, inflammatory markers, and oxidative stress while increasing body weight and antioxidant levels. Additionally, stevia extract manipulated UPR gene expression and reduced apoptosis pathway activation. Histological examination revealed improved liver tissue morphology in stevia-treated diabetic rats. CONCLUSION: These findings suggest that aquatic stevia extract mitigates ER stress in diabetic rats by modulating the IRE-1 arm of the UPR and apoptosis pathways, highlighting its potential therapeutic benefits for diabetes-related liver complications.