New Insights into the Active Structure of Casein-Derived Pentapeptide Ile-Pro-Ile-Gln-Tyr as a Dipeptidyl Peptidase IV Inhibitor In Vivo.

This study investigated the metabolic stability of the casein-derived peptide IPIQY and its active fragments in relation to in vivo hypoglycemic activity. IPIQY dose dependently inhibited DPP-IV activity in Caco-2 cells (IC50 = 73.48 μM). When administered at 300 μmol/kg, IPIQY reduced intestinal and plasma DPP-IV activity by 46.46% and 13.75%, respectively, enhanced plasma insulin levels by 43.42%, and reduced blood glucose levels by 37.77% in OGTT in mice. Metabolic stability results showed IPIQY rapidly entered the bloodstream reaching a peak plasma concentration of 0.51 μM at 2 min after oral administration (300 μmol/kg). It was stable in gastric digestion but degraded into IPIQ and IPI in the intestine. Its low permeability ((4.40 ± 0.18) × 10-8 cm/s) across Caco-2 cells was mainly due to degradation into IP by BBM. IPI was identified as the most active metabolized fragment. The peptides IPIQY, IPIQ, and IPI, all containing active fragment IPI, exhibited comparable hypoglycemic effects in vivo, whereas IP was significantly less active. Furthermore, the gastrointestinal degradation of IPIQY releases active IPI, contributing to its superior hypoglycemic effect via oral administration compared to intravenous injection. These findings provide new insights into the hypoglycemic potential and administration routes of IPIQY.