Mechanistic insights of hypoglycemic components from Polygonatum polysaccharide

TL;DR

This study identifies a specific fraction of Polygonatum polysaccharide that effectively lowers blood sugar by promoting gut-produced short-chain fatty acids and improving insulin sensitivity.

Contribution

The study isolates and characterizes a novel hypoglycemic polysaccharide fraction (PP III) and reveals its mechanism involving gut microbiota and hepatic AMPK activation.

Findings

PP III significantly reduces hyperglycemia and improves insulin sensitivity in diabetic mice.

PP III's mechanism involves gut microbiota-mediated production of acetic and propionic acids, which inhibit hepatic gluconeogenesis.

Propionic acid promotes leptin secretion and activates the AMPK pathway in the liver.

Abstract

This study aimed to fractionate Polygonatum cyrtonema polysaccharide (PP) into distinct components, evaluate their hypoglycemic efficacy using both in vitro and in vivo models, and elucidate the mechanisms of the most active fraction.

Three polysaccharide fractions (PP I, PP II, PP III) were extracted from Polygonatum cyrtonema 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.

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.

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.

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