Macrophage immunometabolic reprogramming impairs tissue regeneration in type 2 diabetes zebrafish model.

Introduction: Type 2 diabetes mellitus (T2D) is a metabolic disorder characterized by chronic hyperglycemia, insulin resistance, and meta-inflammation, which significantly compromise tissue regeneration. Although macrophage dysfunction is implicated in impaired wound healing in T2D, the immunometabolic mechanisms linking hyperglycemia to defective tissue repair remain incompletely understood. Methods: Zebrafish larvae were exposed to hyperglycemic conditions (4% dextrose) to establish a T2D-like model. Survival, glycemic and biochemical parameters were assessed, followed by caudal fin amputation to evaluate regenerative capacity. Total (Mpeg1 Results: Hyperglycemia induced severe metabolic dysregulation, including a 3.5-fold increase in lactate levels and elevated glycemia, and resulted in a 50% reduction in caudal fin regeneration at 72 hours post-injury. Hyperglycemic larvae exhibited a 2.3-fold increase in pro-inflammatory macrophages at the injury site. Ex vivo, macrophages exposed to hyperglycemic conditions showed a 64% reduction in mitochondrial mass, increased mitochondrial ROS production, enhanced glucose uptake, and elevated glycolytic activity, indicating a metabolic shift toward aerobic glycolysis. Discussion: These findings demonstrate that hyperglycemia drives immunometabolic reprogramming of macrophages, sustaining a pro-inflammatory phenotype that impairs tissue regeneration. The zebrafish T2D model provides a robust platform to investigate macrophage-driven immunometabolic mechanisms underlying defective wound healing and to explore therapeutic strategies targeting macrophage metabolism in T2D.