Anti-Diabetic Effect of Soy–Whey Dual-Protein on Mice with Type 2 Diabetes Mellitus Through INS/IRS1/PI3K Signaling Pathway

The effects of soy protein and whey protein supplementation on glycemic control show inconsistency, and the mechanisms underlying the impact of a high-protein diet on blood glucose regulation remain unclear. This study aimed to explore the impact of a dual-protein (DP) blend comprising soy protein isolate (SPI) and whey protein concentrate (WPC), processed through high-pressure homogenization, on mice with Type 2 diabetes mellitus (T2DM) and its potential mechanisms. In the in vitro experiments, an insulin-resistant (IR) HepG2 cell model was treated with DP, resulting in a significant enhancement of glucose uptake and upregulation of IRS1 and GLUT4 expression. For the in vivo experiments, male C57BL/6J mice were randomly assigned into four groups (n = 6) based on body weight: normal control, T2DM model group, Metformin-treated group, and DP-treated group. Following a 5-week feeding period, Metformin and DP significantly reduced levels of blood sugar, AUC, TC, TG, and LDL-C in T2DM mice. Additionally, TP and ALB levels in the DP group were notably higher in the model group. In the liver and pancreas, DP alleviated histopathological changes and promoted liver glycogen synthesis in T2DM mice. Moreover, the levels of IRS1 and PI3K in the livers of mice in the DP group were significantly higher than those in the model group. Compared with the model groups, DP significantly reduced the expression of CD45 and increased the expression of CD206 in the pancreas of mice. Furthermore, 16S rRNA analysis revealed that DP altered the composition of the gut microbiota in diabetic mice, increasing the relative abundance of <i>Lactobacillus</i>, <i>Parvibacter</i>, and <i>Lactobacillaceae</i>. This suggested that DP could alleviate functional metabolic disorders in the gut and potentially reverse the risk of related complications. In conclusion, soy whey dual-protein may have an effective nutritional therapeutic effect on T2DM mice by regulating lipid metabolism, the INS/IRS1/PI3K signaling pathway, and gut microbiota.