Morus alba L. polysaccharide as an mTORC1-targeting agent against type 2 diabetes

Traditional Chinese medicine polysaccharides (TCMPs) have attracted growing attention due to their multi-target and multi-level therapeutic effects in the treatment of diabetes. In this study, we systematically evaluated the antidiabetic effect of three TCMPs, including Moringa oleifera Lam. polysaccharide (MOP), Morus alba L. polysaccharide (MLP) and Lycium barbarum polysaccharide (LBP) in T2DM mouse model. Among the three, MLP exhibited the most pronounced therapeutic efficacy, markedly alleviating hyperglycemia, insulin resistance, hepatic steatosis, and pathological lesions in the liver, pancreas. Liver metabolomic profiling revealed that MLP significantly modulated key glucose and lipid metabolic pathways, particularly bile acid and glycerolipid metabolism. Furthermore, we found MLP exerted its antidiabetic action through inhibition of the mTORC1 signaling pathway, leading to suppressed lipogenesis and enhanced fatty acid oxidation. Notably, MLP-mediated mTORC1 inhibition activated the PPARα–SIRT1 axis, thereby downregulating FOXO1-driven gluconeogenesis and promoting GLUT4-mediated glucose uptake. These findings suggest that MLP exerts comprehensive antidiabetic effects by targeting mTORC1-mediated metabolic reprogramming, offering promise as a natural therapeutic agent for T2DM. • MLP showed the strongest anti-diabetic effects among three tested polysaccharides in T2DM mice. • MLP modulated glucose and lipid metabolism via mTORC1 inhibition and PPARα activation. • MLP presents as a promising natural, low-toxicity therapeutic candidate for T2DM.