Molecular Basis of the Anti-Diabetic Properties of Camel Milk Through Profiling of Its Bioactive Peptides on DPP-IV and Insulin Receptor Activity

Background: The molecular basis of the anti-diabetic properties of camel milk reported in many studies is still elusive. Recent studies reported effects of camel whey proteins (CWPs) and their hydrolysates (CWPHs) on the dipeptidyl peptidase IV (DPP-IV) and the human insulin receptor (hIR) activities. Methods: Pepsin derived CWPHs were generated, screened for DPP-IV inhibitory activity in vitro, and processed for peptide identification by LC-MS/MS. Their binding to DPP-IV was depicted via molecular docking. Furthermore, pharmacological action of the selected hydrolysates on hIR and its signaling were investigated in cell lines using bioluminescence resonance energy transfer, phosphorylation, and glucose uptake assays. Findings: Results showed the inhibition of DPP-IV by CWPs and CWPHs and their positive action on hIR activity. Interestingly, the combination of CWPs or CWPHs with insulin revealed a positive allosteric modulation of hIR that was drastically abolished by the competitive hIR antagonist. Finally, such effects on hIR activity were correlated with an increase in glucose uptake by HepG2 cells. Interpretation: Our data reveal for the first time the profiling and the pharmacological action of CWPs and their derived peptides fractions on hIR and its pathways involved in glucose homeostasis. This sheds more light on the anti-diabetic properties of camel milk by providing the molecular basis that constitutes a solid rationale for the utilization of camel milk in the management of diabetes. Funding Statement: This work was supported by UAEU startup grant (31S305) and UAEU-ZCHS grant (31R235) to MAA, UPAR grant (31F094) to SM, and USM RUI grant (1001/CABR/8011045) to CG. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: Missing.