Complement–Metabolic Inflammation Crosstalk: Molecular Mechanisms and Therapeutic Targets in Type 2 Diabetes and Its Complications

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. 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 and barriers to clinical translation, aiming to offer new insights for precision treatment of T2DM and its complications.