Revisiting the metabolic crosstalk between type 2 diabetes and hyperuricemia: Pathophysiological insights and...

Type 2 diabetes mellitus (T2DM) and hyperuricemia (HUA) are increasingly recognized as interrelated metabolic disorders with shared pathogenic pathways and overlapping complications. Recent epidemiological evidence underscores a growing prevalence of their coexistence, particularly among obese and aging populations. Emerging mechanistic studies reveal a bidirectional relationship: elevated uric acid impairs insulin sensitivity and β-cell function via activation of oxidative stress, inflammation, and urate transporter dysregulation, while insulin resistance reduces renal urate excretion, forming a vicious metabolic cycle. This review comprehensively summarizes the molecular and clinical interplay between T2DM and HUA, with a focus on oxidative stress signaling, RAAS activation, microbiota-derived metabolites, and gene-environment interactions (e.g., SLC2A9 variants). We highlight the therapeutic implications of glucose-lowering agents with urate-modulating properties, such as SGLT2 inhibitors and metformin, and assess the dual metabolic effects of uric acid-lowering agents. Furthermore, the potential of natural compounds-such as polyphenols, flavonoids, and probiotics-is discussed for their multi-target actions on inflammation, insulin signaling, and uric acid metabolism. In addition, recent advances in predictive modeling, microbiota modulation, and precision interventions offer novel avenues for integrated disease management. The integration of pharmacotherapy, lifestyle interventions, and digital health tools may facilitate personalized strategies for this dual metabolic burden. Future research should focus on elucidating causality, refining early diagnostic biomarkers, and developing targeted interventions for comprehensive metabolic control in patients with coexisting T2DM and HUA.