UPLC‐Q/TOF‐MS‐Based Serum Metabolomics Reveals the Potential Antihyperglycemic Mechanisms of Polygonatum sibiricum in KK/Upj‐Ay Type 2 Diabetic Mice

ABSTRACT Polygonatum sibiricum (PS) is a traditional Chinese medicinal herb used as both food and medicinal material. PS is reportedly significantly effective in the treatment of type 2 diabetes mellitus (T2DM) in clinic. However, its pharmacological mechanism and endogenous antihyperglycemic markers remain unknown. This study investigated PS effects in KK/Upj‐Ay 2 diabetic mice and revealed its potential antihyperglycemic mechanisms. Nontargeted serum metabolomics and pathophysiological detection characterized differentially abundant metabolites and determined changes in metabolic pathways. Fasting blood glucose decreased, while serum total cholesterol (TC), tumor necrosis factor‐α (TNF‐α), triglyceride (TG), and whole blood hemoglobin A1c (HbA1c) levels in kidney tissue homogenates were restored to different degrees following administration with PS. Observation of hematoxylin–eosin (HE) staining of the kidney and pancreas, periodic acid‐Schiff (PAS) staining of the kidney, and immunohistochemistry of pancreatic insulin revealed that PS could reduce dysfunction in KK/Upj‐A y 2 diabetic mice. Nontargeted serum metabolomics identified 37 T2DM biomarkers, 27 of which were significantly recovered by high‐dose PS. Further pathway analysis revealed 11 key metabolic pathways involved in PS‐mediated effects. These pathways regulate inflammation, lipid accumulation, oxidative stress, and insulin resistance, elucidating multitarget mechanisms by which PS ameliorates metabolic disturbances and exerts antihyperglycemic effects in KK/Upj‐A y type 2 diabetic mice.