Investigating the anti-diabetic potential of casein through in vitro and computational gene expression analysis: a comparative study with metformin for advancing type 2 diabetes therapy

Abstract

Type 2 diabetes mellitus (T2DM) is a growing global health concern, characterized by insulin resistance and dysregulated glucose metabolism. Current treatments, like metformin, while effective, have limitations in terms of side effects and long-term efficacy. Thus, the exploration of alternative therapeutic agents, such as bioactive peptides from natural sources, has gained attention for their potential in managing T2DM. This study explores the antidiabetic, antioxidant, anti-inflammatory, and anti-hemolytic potential of casein hydrolysate peptides derived from high-purity casein sourced from Fonterra Cooperative Group, New Zealand. The peptides were generated and assessed through a series of in vitro and computational approaches, with metformin serving as a standard control for comparison. In vitro assays revealed that casein hydrolysate peptides demonstrated a dose-dependent inhibition of alpha-amylase, with a maximum inhibition of 95.7% at 500 μg/mL, outperforming metformin’s 77.7% inhibition. Computational analysis of the GSE40234 dataset identified the downregulation of the NCOA2 gene in T2DM patients, with a logFC of -0.89 and a raw P-value of 1.85e-08. Docking studies showed a stronger binding affinity of casein hydrolysate peptides (−9.5 KJ/mol) to NCOA2 compared to metformin (−6.5 KJ/mol). Molecular dynamics simulations confirmed the stability of the casein hydrolysate peptide-NCOA2 complex, supporting its potential as an effective therapeutic agent. These findings highlight casein hydrolysate peptides as a promising candidate for managing T2DM, offering a natural alternative to traditional treatments. Future studies should explore in vivo models and clinical trials to validate these results and further assess the therapeutic potential of casein hydrolysate peptides in diabetes management.