Exploration of the Fasting Hypoglycemic Mechanism of Casein Hydrolysate Enriched with Glu/Gln and Glu/Gln-Containing Peptides in db/db Diabetic-like Mice Using Multiomics Analysis

The fasting hypoglycemic effect of casein hydrolysate (CH) was investigated in db/db diabetic-like mice using a multiomics integrated analysis of peptidome, transcriptome, and metabolome. Results showed that the oral administration of CH at a dose of 600 mg/kg/day for 4 weeks reduced the fasting blood glucose levels by 14.73 ± 9.77%, alleviated insulin resistance (HOMA-IR index) by 36.91 ± 22.62%, and mitigated hepatic damage in db/db diabetic-like mice. Hepatic differential metabolites after CH treatment were enriched in Glu-related metabolites, which acted as substrates for the TCA cycle, enhancing hepatic glucose consumption. The hepatic transcriptomic results revealed that CH treatment upregulated (<i>p</i> < 0.05) hub gene expressions of pparg and pik3cb, leading to an activation of the PPAR signaling pathway, further improving the insulin/PI3K/AKT signaling pathway. The hub gene expressions were highly correlated with Glu-related metabolites in multiomics integrated analysis. Glx/Glx-containing peptides (Glx represents Glu and Gln) in CH, as a dietary supplement to increase hepatic Glu-related metabolites, might be the key active component responsible for its hypoglycemic effect. Particularly, the supplement of Glx was confirmed to effectively (<i>p</i> < 0.05) enhance glucose consumption in hepatocytes. This provides a basis for the development of CHs as functional food.