Molecular Targets and Mechanisms of Casein-Derived Tripeptides Ile-Pro-Pro and Val-Pro-Pro on Hepatic Glucose Metabolism

The objective of this study was to explore the molecular targets and mechanism of Ile-Pro-Pro (IPP) and Val-Pro-Pro (VPP) on regulating glucose metabolism in hepatic cells and their in vivo hypoglycemic activities in mice. Results showed that both IPP and VPP (600 μM) significantly enhanced the glucose consumption in HepG2 cells and primary hepatocytes (p < 0.05). They also regulated activities of glucose metabolizing enzymes and increased the protein expression of p-AKT and GLUT2 in HepG2 cells. IPP directly interacted with the insulin receptor (IR) to activate the insulin/AKT signaling pathway. The activity of VPP on glucose consumption was not attributed to IR binding, and 76 potential antidiabetic targets were predicted by similarity ensemble and shape similarity approaches. Among them, the AKT and MAPK signaling pathway, in which two hub genes AKT1 and MAPK4 existed, were evaluated to make major contributions to the activity of VPP on glucose consumption. Moreover, both IPP and VPP (300 μmol/kg) could significantly reduce the blood glucose levels in mice (p < 0.05), with blood glucose area under the curve dropping by approximately 19% ± 0.09 and 21% ± 0.11%, respectively. This study provides a new theoretical support for the development of IPP and VPP as functional foods to regulate glucose metabolic disorders.