Antihyperglycemic Potential of Quercetin-3-glucoside Isolated from Leucaena leucocephala Seedpods via the SIRT1/AMPK/GLUT4 Signaling Cascade.

Leucaena leucocephala. (Lam.) de Wit, a traditional medicinal plant, has been reported among the ethnic communities of Mexico, Indonesia, China, and India for the treatment of diabetes, obesity, and related complications. This study investigates the antihyperglycemic activity of the plant and its isolated active compound quercetin-3-glucoside. Further, bioactivity guided marker assisted development of an enriched bioactive fraction toward enhancing insulin sensitization was carried out. The enriched fraction was also found to contain 397.96 mg/g of quercetin-3-glucoside along with three other marker compounds, which were also isolated and identified. Quercetin-3-glucoside, out of the four isolated marker compounds from the plant, showed the most significant bioactivity when tested in palmitate-induced insulin-resistant C2C12 myotubes. The compound also showed significant upregulation of sirtuin1 (SIRT1) followed by enhancement of insulin-dependent signaling molecules SIRT1/AMPK/PGC1-α and GLUT4 translocation. Molecular dynamics studies showed the compound having stable interactions with the SIRT1 protein. SIRT1 upregulation has been associated with enhanced insulin sensitivity in skeletal muscle, increasing the glucose uptake by muscle cells. The prepared enriched fraction also modulated the SIRT1/AMPK/GLUT4 pathway. The findings of the present study may find future application toward the development of botanical or phytopharmaceutical drugs from the traditionally important plant L. leucocephala against type II diabetes.