Macrophage immunometabolic reprogramming impairs tissue regeneration in type 2 diabetes zebrafish model
Year: 2026
Type: article
Abstract: 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: ) macrophages were quantified in vivo using confocal microscopy. Additionally, renal-derived macrophages were differentiated ex vivo under normoglycemic or hyperglycemic conditions and analyzed for mitochondrial function, reactive oxygen species (ROS) production, glucose uptake, and glycolytic metabolism using fluorescence probes and Seahorse assays. 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.
Source: Frontiers in Immunology
Authors: Leonel Witcoski Junior, Jordana Dinorá de Lima, André Guilherme Portela de Paula, Thais Sibioni Berti Bastos, Rebeca Bosso dos Santos Luz, Israel Henrique Bini, Matheus Brandemarte Severino, Luis Eduardo Alves Damasceno, Lais Cavalieri Paredes, Amanda Girardi Somensi, Elaine Cristina de Almeida Abreu, Lucas Brito de Souza Santos, Gabriel Costa Lourenço, Mariana Rodrigues Davanso, Rilton Alves de Freitas, Juliana Bello Baron Maurer, Niels Olsen Saraiva Câmara, José Carlos Alves Filho, Karin Braun Prado, Tárcio Teodoro Braga
Language: English
Topic: Wound Healing and Treatments
Subfield: Rehabilitation
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7124453620