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Open Access
Discovery of a novel tetrapeptide as glucose homeostasis modulator with bifunctionalities of targeting DPP-IV and microbiota
Haihong Chen, Wei Li, Wei Hu, Junyu Liu, Canyang Zhang, Yi Wang, Chong Zhang, Xizhen Zhang, Shuo Chen, Qixing Nie, Xinhui Xing
First published: 11 August 2025 https://doi.org/10.1002/imt2.70072

Graphical Abstract
AI-driven and computation-based high-throughput methods were developed to mine novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from hemp seed proteins. The identified peptide VAMP demonstrates a glucose-lowering effect through dual mechanisms: inhibition of DPP-IV activity and selective promotion of intestinal Akkermansia muciniphila growth.

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To the Editor,
Disordered glucose metabolism is closely linked with diabetes, obesity, liver disease, and several cardiovascular diseases [1]. Exploration of effective approaches to alleviate glucose metabolic disorders has gained increasing attention [2]. L cells derived glucagon-like peptide-1 (GLP-1) has been identified to play an important role in glucose homeostasis via stimulating insulin secretion. However, GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP-IV) in the intestine [3].

Currently, one of the important strategies receiving increasing attention is to mine food-derived bioactive peptides from the abundant natural food protein sources for developing DPP-IV bioinhibitors [4]. However, the lack of genomic and proteomic information for many natural protein-containing bioresources also hinders the efficient mining of new DPP-IV inhibitory peptides. Specifically, the main approaches for the mining of DPP-IV inhibitory peptides are labor-, time-, and cost-intensive, including the complicated procedure such as enzymatic protein hydrolysis, separation, purification, identification, and bioactivity examination by synthesis of the target peptides [5]. Therefore, it is challenging to develop a high-throughput integrated mining method which enables effective DPP-IV inhibitory biopeptides to be effectively discovered from natural protein-rich bioresources that can be used in functional food development and peptide medicine innovation.

Hemp (Cannabis sativa L.) is widely farmed and has long been approved for medicinal use in China. Hemp seeds are rich in proteins (20%−25%), which contain various essential amino acids in a desirable ratio [6]. Our previous study indicated that hemp seed protein (HSP) hydrolysates possessed favorable DPP-IV inhibitory effects, but the peptide composition and detailed mechanism have not yet been explored [7, 8]. Moreover, extensive studies have reported that bioactive peptides can improve glucose metabolism by altering gut microbiota. Since the site of action of DPP-IV-inhibiting peptides is primarily the intestine, it is an interesting question if the HSP-derived DPP-IV-inhibiting biopeptides can multifunctionally affect the gut microbiota in the regulation of glucose metabolism. Here, we developed an integrated mining method to mine novel DPP-IV-inhibitory bioactive peptides and investigated their role in the regulation of gut microbiota, offering new insight into biopeptides discovery and hyperglycemia intervention.