Mechanistic insights of hypoglycemic components from Polygonatum polysaccharide

Background: models, and elucidate the mechanisms of the most active fraction. Methods: Hua via ethanol gradient precipitation. The molecular weight distribution and monosaccharide composition were determined using high-performance gel permeation chromatography and pre-column derivatization high-performance liquid chromatography. Hypoglycemic activity was evaluated using insulin-resistant (IR)-HepG2 cells and a db/db mice model. Transcriptomic sequencing and functional enrichment analysis were conducted on PP III-treated db/db mice. Ileocecal short-chain fatty acid contents were quantified by GC-MS. Serum insulin and LEP concentrations were measured via ELISA. Hepatic gluconeogenesis-related gene expression was analyzed using real-time PCR. Results: PP III (31.0% recovery) exhibited distinct monosaccharide composition dominated by rhamnose and glucose, with molecular weights of 1618.4 Da, 477.4 Da, and 309.5 Da, and demonstrated the most pronounced hypoglycemic activity compared to both other fractions and original PP. In db/db mice, PP III administration significantly reduced hyperglycemia while enhancing insulin sensitivity. Transcriptomic sequencing analysis showed that PP III's mechanism involves gut microbiota-mediated short-chain fatty acid production (notably acetic acid and propionic acid), subsequently inhibiting hepatic gluconeogenesis. Mechanistic studies identified propionic acid as a key mediator, which may exert its effects by promoting leptin (LEP) secretion and activating the hepatic AMP-activated protein kinase (AMPK) pathway, thus suppressing hepatic gluconeogenesis. Conclusion: This research identifies PP III as the principal hypoglycemic fraction of PP, providing mechanistic insights and preclinical evidence supporting its potential application as a functional food, health supplement, or pharmaceutical agent for diabetes management.