Abstract
Hyperuricemia, associated with gout and uric acid nephrolithiasis (FitzGerald et al., 2020; Li et al., 2014), is recognized as a contributor to metabolic dysfunction (Borghi et al., 2021; Ali, 2026). Evidence indicates a bidirectional relationship between serum uric acid (SUA) and insulin resistance (IR) (Sun et al., 2021; Xu et al., 2016; Oh and Cho, 2025; Sakallı et al., 2023). Intracellular uric acid may promote metabolic dysfunction through reactive oxygen species (ROS), endothelial nitric oxide synthase (eNOS) uncoupling, endoplasmic reticulum (ER) stress, NLRP3 inflammasome activation, and de novo lipogenesis (Ali, 2026; Park et al., 2023; Wu et al., 2020; Choi et al., 2014; Lanaspa et al., 2012). Conversely, hyperinsulinemia may reduce renal urate clearance by increasing GLUT9a/b and URAT1 activity (Li et al., 2014; Sun et al., 2021; Mandal et al., 2021). Elevated SUA is associated with increased risk of type 2 diabetes mellitus (T2DM) and metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), and diabetic kidney disease (DKD) (Borghi et al., 2021; Xu et al., 2016; Ford et al., 2007; Alanazi, 2025; Bhole et al., 2010; Kramer et al., 2009). Randomized controlled trial evidence regarding urate-lowering therapies (ULT) and insulin resistance remains inconsistent (Zhao and Zhao, 2026; Perez-Pozo et al., 2010; Takir et al., 2015; Beddhu et al., 2016). SGLT2 inhibitors and GLP-1 receptor agonists provide metabolic benefits and enhance renal urate excretion (Mandal et al., 2021; de Boer et al., 2022; Chino et al., 2014). This review summarizes uric acid physiology, insulin signaling, mechanisms, evidence, and therapeutic implications.