Isorhamnetin Exhibits Hypoglycemic Activity and Targets PI3K/AKT and COX-2 Pathways in Type 1 Diabetes

<b>Background:</b> Isorhamnetin (ISO), a dietary O-methylated flavonol, was evaluated for hypoglycemic activity and mechanism in a streptozotocin (STZ) model of type 1 diabetes. <b>Methods:</b> We conducted untargeted plasma metabolomics (ESI±), network integration and docking, and measured pancreatic PI3K, phosphorylated AKT, and COX-2; INS-1 β cells challenged with the PI3K inhibitor LY294002 were used to assess viability, intracellular ROS, and PI3K phosphorylation. <b>Results:</b> ISO lowered fasting glycemia, increased circulating insulin, improved dyslipidemia by reducing low-density lipoprotein cholesterol (LDL-C), and preserved islet architecture. Untargeted plasma metabolomics (ESI±) indicated broad remodeling with enrichment of arachidonic-, linoleic-, starch/sucrose- and glycerophospholipid pathways. Network integration and docking prioritized targets converging on PI3K/AKT and COX-2/eicosanoid signaling. Consistently, in pancreatic tissue, ISO increased PI3K, phosphorylated AKT, and reduced COX-2. In INS-1 beta cells challenged with the PI3K inhibitor LY294002, ISO improved viability, decreased intracellular ROS, and partially restored PI3K phosphorylation at 4 µM. <b>Conclusions:</b> Together, these data indicate that ISO exerts hypoglycemic effects while supporting β-cell integrity through activation of PI3K/AKT and tempering of COX-2-linked lipid-mediator pathways. ISO therefore emerges as a food-derived adjunct candidate for autoimmune diabetes, and the work motivates targeted lipidomics and in vivo pathway interrogation in future studies.