Multi-Target Antidiabetic Potentials of Xylocarpus mekongensis: In Vivo Efficacy, Enzyme Inhibition, and Molecular Docking.

Xylocarpus mekongensis Pierre (Meliaceae), locally known as "Poshur" is a mangrove plant traditionally used in South and Southeast Asia for the management of diabetes and related disorders. This study comprehensively evaluated the phytochemical composition, safety, antidiabetic efficacy, enzymatic inhibition, and in-silico molecular docking analysis of its ethanolic bark extract. HPLC-DAD profiling identified six major phenolic compounds - catechin hydrate, catechol, (-) epicatechin, syringic acid, trans-ferulic acid, and trans-cinnamic acid. Acute and subacute toxicity assessments in Swiss albino mice (following OECD guidelines) confirmed its safety up to 3000 mg/kg without any physiological or behavioral alterations. In the oral glucose tolerance test (OGTT), the extract significantly reduced blood glucose levels in a dose-dependent manner. In streptozotocin (STZ)-induced diabetic mice, daily oral administration of the extract (250 and 500 mg/kg) markedly reduced fasting blood glucose, restored body weight, and normalized hepatic, renal, and lipid biomarkers comparable to glibenclamide. Moreover. the extract also demonstrated potent α-glucosidase inhibitory activity (IC50 = 0.420 mg/mL), indicating delayed intestinal glucose absorption. Molecular docking revealed strong binding affinities of these compounds-particularly catechin hydrate and (-) epicatechin demonstrated strong binding affinities with key diabetic targets, including sulfonylurea receptor 1 (SUR1), peroxisome proliferator-activated receptor gamma (PPAR-γ), dipeptidyl peptidase-4 (DPP4), glucokinase, and AMP-activated protein kinase (AMPK), suggesting multi-targeted modulation of insulin secretion, sensitivity, and glucose utilization. These findings provide the first comprehensive mechanistic validation of the traditional use of X. mekongensis and highlight its polyphenolic constituents as promising natural leads for developing multi-target antidiabetic therapeutics.