Pakistan Journal of Pharmaceutical Sciences

Abstract: Background: Type 2 diabetes involves insulin resistance, where muscle, liver, and fat cells fail to utilize glucose leading to hyperglycemia. Objectives: This study explores the therapeutic potential of pulegone in type 2 diabetes by examining its molecular interactions with key metabolic targets and evaluating its effects on insulin resistance and inflammatory cytokine modulation. Methods: Except for normal controls, animals were fed a high-sucrose, high-fat diet for four months to induce insulin resistance. Treatment groups received metformin (150?mg/kg) or pulegone doses: low (5?mg/kg), medium (10?mg/kg), and high (15?mg/kg) for 45 days. Post-treatment, tissues and blood were collected. Blood serum was analyzed for liver markers, lipid profile, and blood for glycated hemoglobin. ELISA was used for cytokines (resistin, adiponectin, IL-1Ra, TNF-?), and qPCR assessed gene expression of NF-?B, TNF-?, PPAR-?/?, IL-6, IL-10, IL-1Ra, and adiponectin. Histopathology was performed. Data were analyzed using GraphPad Prism. Molecular docking was conducted to identify the binding affinities of pulegone to target proteins. Results: Pulegone significantly reduced fasting blood glucose, glycated hemoglobin, triglycerides, cholesterol, and liver enzymes, while increasing HDL levels compared with diabetic controls. It also decreased serum resistin, TNF-?, IL-6 and NF-?B expression, while upregulating adiponectin, IL-10, PPAR-?, PPAR-? and IL-1Ra. Histopathological examination showed protective effects on the pancreas, liver, kidney, heart, and aorta. Docking analysis favored strong binding affinities of pulegone with key targets. Conclusion: Pulegone ameliorates insulin resistance by improving glycemic and lipid profiles, modulating pro- and anti-inflammatory cytokines, and protecting vital organs, suggesting its potential as a multitarget antidiabetic agent.