PPAR-γ as a therapeutic target: role of plant-derived bioactive compounds in diabetes mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder characterized by insulin resistance, impaired insulin secretion, chronic inflammation, oxidative stress, and dysregulated lipid metabolism. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a ligand-activated nuclear receptor, plays a central role in regulating glucose homeostasis, lipid metabolism, adipocyte differentiation, and insulin sensitivity, making it an important therapeutic target for diabetes management. Although synthetic PPAR-γ agonists, particularly thiazolidinediones, effectively improve glycemic control, their clinical use is limited by adverse effects such as weight gain, fluid retention, cardiovascular complications, hepatotoxicity, and concerns related to long-term safety. Consequently, increasing attention has been directed toward plant-derived bioactive compounds as safer and more selective PPAR-γ modulators. This review summarizes recent advances in the identification and characterization of plant-derived phytochemicals with PPAR-γ modulatory activity and discusses their molecular mechanisms in diabetes management. A diverse range of phytoconstituents, including flavonoids, phenolic acids, terpenoids, alkaloids, lignans, coumarins, stilbenes, and phytosterols, have demonstrated the ability to enhance insulin sensitivity, promote glucose uptake, regulate adipogenesis and lipid metabolism, suppress inflammatory signaling, and reduce oxidative stress through selective or partial modulation of PPAR-γ. Emerging evidence from in vitro, in vivo, and in silico studies highlights their potential as promising alternatives or adjuncts to conventional antidiabetic therapies. Furthermore, advances in computational drug discovery, network pharmacology, molecular docking, artificial intelligence-assisted screening, and nanotechnology-based delivery systems are accelerating the development of novel plant-derived selective PPAR-γ modulators with improved efficacy and bioavailability. Despite these promising findings, well-designed preclinical and clinical studies are required to validate their therapeutic efficacy, safety, pharmacokinetic properties, and long-term clinical applicability for the management of T2DM and its associated metabolic complications.