Structural characterization and hypoglycemic mechanism of Chinese yam polysaccharide at the nexus of IR-AMPK-PI3K-AKT pathway in type 2 diabetic zebrafish and cellular insulin resistant model.

Chinese yam polysaccharides (CYPS) have attracted significant interest for their potential health benefits, particularly in managing diabetes mellitus (T2DM). However, their structural characteristics, antidiabetic mechanisms in insulin-resistant cells, and type 2 diabetic models remain poorly understood. This study aimed to elucidate the structural properties of CYPS using various analytical techniques and to evaluate its antidiabetic mechanism in an insulin-resistant cellular model and a type 2 diabetic zebrafish pre-clinical model. The results demonstrated that CYPS is a neutral pyranose-type polysaccharide containing both α- and β-glycosidic linkages with a random coil conformation. It is a polydisperse mixture comprised of 15 monosaccharides, including D-sorbitol, D-galactose, d-glucose, inositol, and D-mannose. CYPS significantly improved glucose uptake and increased the activity of hexokinase and pyruvate kinase in dexamethasone-induced insulin-resistant 3 T3-L1 adipocytes. Moreover, CYPS treatment markedly reduced whole-larvae glucose levels, ameliorated dyslipidemia, and improved the activities of hexokinase and pyruvate kinase to support glucose metabolism. CYPS also reduced oxidative stress by increasing glutathione peroxidase activity and decreasing malondialdehyde levels. Mechanistically, CYPS enhanced the expression of PI3K, Akt, AMPK, and IRS1 in diabetic zebrafish and dexamethasone-treated insulin-resistant cells - key factors for insulin sensitivity, glucose metabolism, energy balance, and downstream cellular functions. Thereby, it influences important genes and proteins within the AMPK-PI3K/Akt signaling pathway. These findings strongly suggest that polydisperse CYPS significantly improves insulin sensitivity and glucose homeostasis in type 2 diabetic zebrafish by targeting AMPK-PI3K/Akt pathway and could be a promising candidate to be explored further as a functional therapeutic food for T2DM management.