Antidiabetic potential of Mentha piperita essential oil: GC–MS profiling, in vitro, in vivo and in silico analyses

• Mentha piperita essential oil (EO) exhibited strong anti-diabetic effects in vitro and in vivo. • GC-MS identified 34 major compounds, including α-terpineol, eucalyptol, and linalool acetate. • Molecular docking and dynamics predicted stable binding of EO components to α-amylase and α-glucosidase. • ADMET and DFT analyses confirmed drug-like properties and safety of key compounds. • Results support M. piperita EO as a natural candidate for diabetes management. In this study, Mentha piperita essential oil (EO) antidiabetic activity was thoroughly investigated using a multidisciplinary approach. Gas chromatography–mass spectrometry (GC–MS) identified some key bioactive compounds, including pulegone, α-terpineol, borneol, linalool acetate, menthone, eucalyptol, and trans-sabinene hydrate. Their relative percentages in the EO (>1% w/w) were indicative of biological importance. In vitro enzyme inhibitory assays displayed strong inhibitory effects of the EO on the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase and stronger inhibitory action than the standard antidiabetic compound acarbose. In vivo research in diabetic rats induced by alloxan monohydrate reaffirmed the hypoglycemic effect of the EO with the lowering of fasting blood glucose level by 33% after 14 days of treatment. Molecular docking experiments indicated greater binding affinities of pulegone for α-amylase (ΔG = –5.83 kcal·mol⁻¹) and linalool acetate for α-glucosidase (ΔG = –6.95 kcal·mol⁻¹) compared to acarbose (ΔG = –4.51 and –6.09 kcal·mol⁻¹, respectively). Molecular dynamics simulations also validated the structural stability and optimal interaction dynamics of principal EO components with α-amylase and α-glucosidase. Eucalyptol and linalool acetate possessed minimum root-mean-square deviation (RMSD) and solvent-accessible surface area (SASA) against α-amylase, showing high stability of complex, while α-terpineol and eucalyptol exhibited good binding affinity towards α-glucosidase. MM-PBSA binding free energy calculations revealed that linalool acetate and eucalyptol were the best inhibitory agents for α-amylase (–26.98 and –26.45 kcal·mol⁻¹) and α-glucosidase (–20.41 and –20.71 kcal·mol⁻¹), respectively. DFT analysis also yielded more insight into their electronic properties, reactivity, and stability, further establishing their enzyme inhibition activity. These findings introduce M. piperita EO as a natural agent with α-amylase and α-glucosidase inhibition potential for the management of diabetes and glycemia. This study highlights the anti-diabetic potential of Mentha piperita essential oil through integrated in vitro, in vivo, and in silico approaches. Key compounds showed strong enzyme inhibition, favorable pharmacokinetics, and stable molecular interactions, supporting their role as natural inhibitors of α-amylase and α-glucosidase.