Insulinotropic and Beta-Cell Proliferative Effects of Unripe <em>Artocarpus heterophyllus</em> Extract Ameliorate Glucose Dysregulation in High-Fat-Fed Diet Induced Obese Mice

Artocarpus heterophyllus, familiar as jackfruit, is a tropical fruit highly valued not only for its nutritional content but also for its medicinal properties, including potential antidiabetic effects. In this study, ethanolic extract of unripe Artocarpus heterophyllus (EEAH) exhibited significant antidiabetic activity through multiple mechanisms. EEAH enhanced glucose-stimulated insulin secretion in BRIN-BD11 &beta;-cells via KATP channel modulation and cAMP-mediated pathways, with partial dependence on extracellular calcium, and it also promoted &beta;-cell proliferation. In vitro assays revealed its ability to inhibit starch digestion and glucose diffusion, indicating delayed carbohydrate digestion and absorption. In high-fat-fed (HFF) obese mice, Acute and chronic oral administration of EEAH improved oral glucose tolerance, reduced fasting blood glucose, decreased body weight, and normalized food and fluid intake. Lipid profile analysis showed increased HDL and reduced total cholesterol, LDL, and triglycerides, while higher doses of EEAH also enhanced gut motility. Phytochemical screening revealed the presence of bioactive compounds such as alkaloids, tannins, flavonoids, saponins, steroids and, terpenoids, which are likely responsible for these therapeutic effects. These findings highlight EEAH as a promising natural candidate for adjunctive therapy in managing type 2 diabetes and associated metabolic disorders and emphasize the importance of future multi-omics studies to elucidate its molecular targets and pathways.