Structural characterization and systemic hypoglycemic effects of a new high-molecular-weight α-glucan from Grifola frondosa.

Despite increasing evidence supporting the promising anti-diabetic potential of natural polysaccharides, studies on structurally well-defined polysaccharides and their systemic mechanisms of action in type 2 diabetes mellitus (T2DM) remain limited. Here, we characterize GFP-Z, a bioactive α-glucan (1760.0 kDa) isolated from Grifola frondosa, which features an α-1,4-linked backbone with α-1,6, α-1,3 and α-1,2 branches. Pharmacological evaluation in db/db mice showed that GFP-Z administration significantly alleviated hyperglycemia and diabetic symptoms, with glucose-lowering effects comparable to metformin under the tested conditions, without causing apparent hepatorenal toxicity. Integrated multi-omics analyses, biochemical assays, and a preliminary pharmacological attenuation experiment further suggest that GFP-Z may exert its effects, at least in part, through immunomodulation-associated metabolic regulation, as reflected by reduced hepatic M1-type macrophage infiltration, altered circulating cytokines and hepatic immunometabolites, activation of the hepatic JAK/STAT-PI3K/AKT signaling axis, and attenuation of GFP-Z-associated immune and glucose-lowering responses by tofacitinib. Taken together, our findings suggest that GFP-Z may represent a promising bioactive polysaccharide capable of improving metabolic disorders in T2DM, potentially through systemic immunomodulation-associated metabolic regulation.