Milk peptides found in human jejunum induce CCK and GLP-1 secretion and inhibit DPP-IV

Resumen del trabajo presentado a la 8th International Conference on Food Digestion, celebrada en Porto (Portugal) del 9 al 11 de abril de 2024.

During food ingestion, gastrointestinal hormones such as glucagon-like peptide-1 (GLP-1) and cholecystokinin (CCK) are released in response to nutrients. GLP-1 has a short life due to its degradation by the aminopeptidase dipeptidyl peptidase-IV (DPP-IV), which is expressed at the gastrointestinal tract with maximum secretion in jejunum and ileum, and also circulates in plasma. The role of the DPP-IV enzyme as well as GLP-1, are crucial in glucose homeostasis, especially in type-2 diabetic patients. This work aims to characterize the DPP-IV inhibitory activity and GLP-1/CCK secretagogue effect of peptides derived from the major milk proteins previously found in human jejunal digests after casein or whey oral ingestion. GLP-1 and CCK secretion was evaluated in STC-1 enteroendocrine cells while DPP-IV inhibition was assayed in non-differentiated Caco-2 cells. The intracellular calcium concentration was measured in order to study STC-1 cell activation. Hormone secretion was found to be sequence-specific. For instance, the consecutive loss of amino acids at the N-terminal end of the peptide 6LNVPGEIVE14 reduced stepwise CCK secretion. This same event occurred for peptide 81PVVVPPFLQPE91 where deletion of proline at the N-terminal end reduced both CCK and GLP-1 secretion. However, for peptides 172LPVPQ175 and 59VYPFPGPIPN68 the loss of amino acids at the N-terminal end increased GLP-1 and CCK release. Regarding DPP-IV enzyme inhibition, sequences derived from β-casein 8VPGEIVE14, 85PPFLQPE92, 89QPEV92, 60YPFPG64, and 60YPFPGPI66 were shown to have a strong inhibitory potential on the DPP-IV enzyme, supporting the important role of proline in second Nterminal position for this inhibitory effect. In conclusion, peptide sequences found in human jejunum after ingestion of milk proteins are able to significantly stimulate CCK and GLP-1 secretion, while inhibiting DPP-IV, which is important to reduce hormone degradation. Therefore, these sequences have been shown to have the potential to control postprandial glycemia.

This work has received financial funding from projects PID2019-107663RB-100 and PDC2022-133489-100 (Spanish Ministry of Science and Innovation MICINN/AEI/10.13039/501100011033) and the latter counting with funding from European Union NextGenerationEU/PRTR. CGM is the recipient of the contract (PIE 202270E126) from CSIC.

Peer reviewed