Abstract: To investigate the anti-diabetic effect of β-(1,3)-glucan and the underlying biological mechanism, a diabetic mouse model was established by high-fat-diet (HFD) feeding combined with streptozotocin (STZ) injection. Four groups of mice were set up: a normal, model, and metformin-treated, and CMP33 (a carboxymethylpachymaran from Poria coco)-treated group. Changes in body mass, organ indices, blood glucose and lipid metabolism indicators, inflammatory indicators, and hepatic oxidative stress indicators were measured. Additionally, proteomic analysis of the liver of mice in the model and CMP33 groups was performed using data-independent acquisition (DIA). The results showed that CMP33 alleviated body mass loss, mitigated liver and pancreas damage, effectively reduced blood glucose, glucose tolerance, glycated hemoglobin, and triglyceride levels, and increased insulin levels in diabetic mice, exhibiting potent anti-diabetic effect. DIA-based proteomics identified 255 differentially expressed proteins (DEPs), including 134 upregulated and 121 downregulated proteins. Bioinformatic analysis revealed that these DEPs primarily participated in biological process such as lipid metabolism regulation, nucleotide catabolism, autophagy, insulin signaling, and glucose transport and were primarily enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to diseases (such as cancer, metabolic diseases, and neurodegenerative diseases), metabolic regulation, and signal transduction pathways, underscoring that CMP33 protected against diabetes through a multi-target and multi-pathway mechanism. Protein-protein interaction analysis highlighted that GTPase HRas, histone-lysine N-methyltransferase 2D, NEDD8 ultimate buster 1, histone H2A type 1, long-chain fatty acid transport protein 1, ATP-citrate synthase, and acetyl-coenzyme A synthetase might be the key proteins responsive to CMP33. These results demonstrate the anti-diabetic effect of β-(1,3)-glucan and provide insights into the underlying biological mechanism from a proteome perspective. The findings expand our understanding of the mechanisms by which polysaccharides exert anti-diabetic effects and offer a scientific basis for the application of β-(1,3)-glucan in functional foods for diabetes management.

Key words: β-(1,3)-glucan; glucose metabolism; lipid metabolism; proteomics; differentially expressed proteins