Peel of Pomegranate Fruit (Punica granatum) Improves Glucose Homeostasis in Obese Mice: An Integrated In Vitro, In Vivo, and In Silico Molecular Docking Study

Pomegranate (Punica granatum), a shrub belonging to the Lythraceae family, has long been recognized for its diverse pharmacological benefits, including potential roles in managing inflammation and diabetes. The present study explored the insulin-secretory and β-cell proliferative properties of the ethanol extract of P. granatum fruit peel (EEPG) and assessed its influence on glucose regulation in high-fat-fed diet-induced obese mice (HFDi-OM) through in vivo and in silico studies. In vitro, EEPG was found to activate cAMP-dependent pathways and regulate KATP channels, thereby enhancing glucose-stimulated insulin secretion from BRIN-BD11 β-cells, with partial reliance on extracellular calcium. EEPG promoted β-cell proliferation, as indicated by an increase in Ki-67 positive cells, and displayed inhibitory effects on glucose diffusion and starch hydrolysis, suggesting a capacity to delay carbohydrate digestion and absorption. Furthermore, EEPG demonstrated antioxidant activity by neutralizing free radicals. In an acute test, EEPG (at doses of 150 and 250 mg/5 mL/kg) improved oral glucose tolerance and elevated plasma insulin levels. Long-term oral treatment for 21 days to HFDi-OM led to a significant reduction in fasting blood glucose, body weight, and food and fluid intake. It also enhanced gastrointestinal motility and improved lipid profiles by increasing HDL and lowering total cholesterol, LDL, and triglycerides. The therapeutic properties of EEPG are likely attributed to its rich bioactive components, including flavonoids (quercetin, kaempferol, catechin, and epicatechin) and phenolic acids (ellagic acid), which exhibited strong multi-target binding affinities in in silico molecular docking studies toward SUR1, PDE4, PI3K, and α-amylase, thereby supporting enhanced insulin secretion, β-cell function and glucose homeostasis.