Longan seed-derived peptides inhibit glucose transport via modulation of SGLT1 and GLUT2 in Caco-2 cells

This study presents the first evidence of the ability of two synthetic peptides, SA-10 (SSYYPFKGFA) and VI-10 (VKGPGLYSDI), derived from longan seed hydrolysates to inhibit intestinal glucose absorption via SGLT1 and GLUT2 transporters. Molecular docking revealed strong binding affinities: SA-10 to SGLT1 (-9.1 kcal/mol) and VI-10 to GLUT2 (-8.7 kcal/mol), involving hydrogen bonds and hydrophobic interactions at key glucose-binding sites, suggesting competitive inhibition. Molecular dynamics simulations over 100 ns supported these findings, demonstrating structural stability and compactness of the peptide-transporter complexes, as indicated by sustained RMSD and Rg values throughout the simulation trajectory. In vitro assays using Caco-2 cells showed that both peptides significantly reduced glucose uptake in a dose- and time-dependent manner, achieving approximately 50% reduction at 1.00 mM after 3 h. Western blot analysis confirmed SA-10 downregulated SGLT1 expression, while VI-10 reduced both SGLT1 and GLUT2 levels. These findings suggest that longan seed-derived peptides can modulate both glucose uptake and transporter expression in intestinal cells. Importantly, SA-10 and VI-10 represent novel glucose transporter inhibitors and hold promise for development as functional food ingredients or nutraceuticals to manage postprandial hyperglycemia and support glycemic control in diabetes management. Longan seed-derived peptides SA-10 and VI-10 inhibit glucose uptake in intestinal cells by targeting SGLT1 and GLUT2. These peptides reduce glucose transport and suppress the expression of both transporters, showing potential anti-diabetic effects. • SA-10 and VI-10 peptides from longan seeds inhibit glucose uptake via SGLT1 and GLUT2. • SA-10 binds strongly to SGLT1 (-9.1 kcal/mol); VI-10 to GLUT2 (-8.7 kcal/mol). • MD simulations demonstrate the structural stability of the transporter-peptide complexes. • Up to ∼50% glucose uptake reduction in Caco-2 cells at 1.00 mM after 3 hours. • SA-10 downregulates SGLT1; VI-10 reduces both SGLT1 and GLUT2 expression. • Potential for use in functional foods for glycemic control.