A novel bifunctional peptide VAMP mined from hemp seed protein hydrolysates improves glucose homeostasis by inhibiting intestinal DPP-IV and increasing the abundance ofAkkermansia muciniphila

Discovery of new dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from natural protein resources capable of regulating glucose metabolism in type 2 diabetic populations has been a significant challenge. In this study, we constructed a molecular docking- and machine learning-aided DPP-IV inhibitory peptide library and combined a functional screening approach based on intestinal organoids to discover efficient and new DPP-IV-inhibiting peptides from hemp seed protein hydrolysates. A novel tetrapeptide, VAMP, was then identified to strongly inhibit DPP-IV (IC 50 =1.00 μM in vitro ), which competitively binds to DPP-IV and improves glucose metabolism in vivo with high safety by increasing active glucagon-like peptide-1 (GLP-1) levels in obese mouse models. Interestingly, VAMP specifically promoted the growth and abundance of intestinal Akkermansia muciniphila in vivo , at the same time, which was responsible for the improved intestinal barrier function and insulin resistance. Our study demonstrated that the novel bifunctional VAMP can effectively target the DPP-IV-GLP-1 axis and simultaneously regulate the abundance of the gut microbial A. muciniphila , to regulate glucose homeostasis, providing a promising nutraceutical and therapeutic tetrapeptide for hyperglycaemia treatment by targeting the gut-microbiata axis. Teaser VAMP improves glucose metabolism by increasing the active GLP-1 level and promoting the growth of A. muciniphila to improve intestinal barrier function.