Complement-Metabolic Inflammation Crosstalk: Molecular Mechanisms and Therapeutic Targets in Type 2 Diabetes and Its...

Type 2 diabetes mellitus (T2DM), a global metabolic disease, is fundamentally characterized by a vicious cycle of chronic low-grade inflammation and metabolic dysregulation. The complement system, a key effector of innate immunity, has recently been recognized as deeply involved in initiating and amplifying metabolic inflammation. Although current studies have revealed critical roles of complement components in pancreatic β-cell damage, insulin resistance, and adipose tissue inflammation, the interactive network between complement and metabolic inflammation in T2DM microvascular and macrovascular complications remains incompletely understood, and complement-targeted therapies still face specificity and safety challenges, including systemic immunosuppression risks. This review systematically summarizes the molecular crosstalk between complement components and metabolic inflammation in T2DM and its complications, focusing on complement-mediated β-cell apoptosis, suppression of insulin signaling, adipose tissue macrophage polarization, and renal and vascular endothelial injury. We also discuss the prospects of complement-targeted drug development, highlighting key candidate targets such as C3aR, C5aR1, and Factor B, as well as primary translational bottlenecks including systemic immunosuppression risks, infection susceptibility, and limited target specificity, aiming to offer new insights for precision treatment of T2DM and its complications.