Fu-Fang-Qi-Di-Hua-Yu-Tang Improves Diabetic Macrovascular Disease via PI3K/AKT Pathway Regulation

Objective This study aimed to investigate the active ingredients and mechanisms of Fu-Fang-Qi-Di-Hua-Yu-Tang (FFQD) in alleviating atherosclerosis and insulin resistance in diabetic macrovascular disease (DMD) mice.Methods Chemical profiling of FFQD was performed using UPLC-Q-TOF-MS. Apoe-/- mice were injected with streptozotocin and fed a high-fat diet to establish DMD. Groups included control (C57BL/6), model (normal saline), low/medium/high-dose FFQD, and western medicine (atorvastatin + metformin). After 12 weeks, aortic morphology, blood glucose/lipid profiles, inflammatory factors, and PI3K/AKT pathway-related targets were analyzed.Results FFQD contained 159 identified components. Treatment significantly reduced aortic plaque area, blood glucose, lipids, and lowered the levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), oxidized low-density lipoprotein (ox-LDL), C-reactive protein (CRP), and monocyte chemoattractant protein-1 (MCP-1). It also reduced nitric oxide synthase 2 (NOS2) level, a marker of macrophage polarization, increased arginase 1 (Arg1) level, regulated macrophage polarization, and improved oxidative stress and inflammatory response. In addition, FFQD activated the receptor for advanced glycation end products (RAGE)/PI3K/AKT/mammalian target of rapamycin (mTOR) pathway in the aorta, inhibited RAGE expression, promoted PI3K, AKT, and mTOR phosphorylation, down-regulated microtubule-associated protein 1A/1B-light chain 3-II/I (LC3 II/I) and nuclear factor κB (NF-κB p65) expression, up-regulated SQSTM1 protein (p62) expression, inhibited excessive autophagy, and reduced vascular endothelial damage caused by long-term high glucose levels. In the liver, FFQD activated the Ras family small molecule G protein (RAP1)/PI3K/AKT/forkhead box protein 01 (FOX01) pathway, inhibited RAP1 expression, promoted PI3K and AKT phosphorylation, suppressed FOX01 expression, and improved insulin resistance.Conclusion FFQD may improve insulin resistance, regulate glucose and lipid metabolism, inhibit excessive autophagy, induce macrophage polarization, resist inflammation and oxidative stress, inhibit atherosclerosis, and ultimately improve DMD by activating the RAGE/PI3K/AKT/mTOR and RAP1/PI3K/AKT/FOX01 pathways. Therefore, FFQD may be a promising candidate for DMD treatment.