Edible Yellow Mealworm-Derived Antidiabetic Peptides: Dual Modulation of α-Glucosidase and Dipeptidyl-Peptidase IV Inhibition Revealed by Integrated Proteomics, Bioassays, and Molecular Docking Analysis.

Type 2 diabetes mellitus (T2DM) poses a critical global health burden, necessitating safer multi-target therapies. We pioneer the exploration of novel bioactive peptides from Tenebrio molitor larvae-an underexplored, sustainable, and edible insect protein-through proteomics-guided screening and bioassays. Six unique peptides (DK-7, WK-6, GR-7, FK-8, SK-6, and DK-8) demonstrated significant α-glucosidase and dipeptidyl-peptidase IV (DPP-IV) inhibitory effects, and significant glucose consumption enhancement in insulin-resistant HepG2 cells. Molecular docking revealed a binding topology where peptides interacted with α-glucosidase at its active sites (Glu271, Arg643, Arg647, Arg653, Tyr733, Lys765, and Glu767) and with DPP-IV at active residues (Phe357, Tyr547, Trp629, Asp729, and Gln731) through dual hydrogen-bond networks and hydrophobic interactions, establishing a novel inhibition mechanism. We wish to propose that insect-derived biopeptides have potential value as next-generation therapeutics, simultaneously advancing sustainable drug discovery and approximating functional food bioresources to biomedicine.