Molecular mechanisms and structure—activity relationships of natural polysaccharides in ameliorating type 2 diabetes mellitus: a comprehensive review

Type 2 diabetes mellitus (T2DM) is a global metabolic pandemic affecting hundreds of millions of people, with current pharmacological therapies limited by adverse effects, long-term tolerability issues, and cost barriers. Natural polysaccharides-high-molecular-weight carbohydrate polymers derived from plants, fungi, marine organisms, and animal sources-have emerged as a promising class of multi-target bioactive agents for T2DM management. This comprehensive review first outlines the key pathophysiological mechanisms of T2DM, encompassing insulin resistance, pancreatic β-cell dysfunction, chronic inflammation, oxidative stress, and gut microbiota dysbiosis. We then systematically review the natural sources and structural classification of polysaccharides, alongside their extraction and purification methods. The core of this review examines the molecular mechanisms by which natural polysaccharides ameliorate T2DM: (1) enhancing insulin sensitivity and glucose metabolism via the PI3K/Akt and AMPK signaling pathways; (2) protecting pancreatic β-cells from apoptosis and promoting insulin secretion; (3) suppressing chronic inflammation through NF-κB and NLRP3 pathway inhibition; (4) attenuating oxidative stress via Nrf2/HO-1 pathway activation; and (5) restoring gut microbiota homeostasis, reinforcing intestinal barrier integrity, and elevating short-chain fatty acids production. Structure-activity relationship analyses indicate that hypoglycemic efficacy is tightly correlated with molecular weight, monosaccharide composition, glycosidic linkage types, degree of branching, three-dimensional conformation, and chemical derivatization. Finally, challenges surrounding clinical translation, standardization, and bioavailability are discussed, along with future research directions. This review provides a theoretical framework for the application of natural polysaccharides as functional foods, nutraceuticals, or lead compounds in T2DM prevention and treatment.