Branched-chain amino acid metabolism and macrophage polarization: potential regulatory nodes and therapeutic targets in diabetes-associated metabolic inflammation

Abstract

T2DM is characterized by chronic low-grade metabolic inflammation, and imbalanced macrophage polarization is a key immunological mechanism contributing to insulin resistance (IR), pancreatic β-cell damage, and diabetes progression. Recent studies in immunometabolism suggest that BCAA metabolism regulates macrophage polarization in a context-dependent manner. Physiological BCAA catabolism supports M2-like oxidative metabolism and repair functions, whereas chronic overload of BCAA and its catabolic metabolites in diabetes may promote pro-inflammatory responses through multiple pathways. Disruptions in BCAA metabolism mediate the remodeling of macrophage immunometabolism and polarization imbalance, thereby inducing the onset and progression of metabolic inflammation in diabetes. Accordingly, this study will conduct a systematic literature search in PubMed, Web of Science, and Google Scholar to review the mechanisms by which BCAA metabolic disorders in diabetes mediate the immunometabolic reprogramming of macrophages and regulate the imbalance in M1/M2 polarization. Current evidence suggests that BCAA metabolic dysregulation can drive macrophage metabolic reprogramming through multiple pathways, leading to an imbalance in M1/M2 polarization and promoting diabetes-associated metabolic inflammation. Importantly, interventions including low-BCAA diets, caloric restriction, exercise, activators of BCAA catabolism, PPARγ agonists, berberine, ginsenoside Rb1, mulberry leaf and twig extracts, probiotics, and other gut microbiota-targeted strategies have shown potential to modulate BCAA metabolism, improve insulin sensitivity, and alleviate metabolic inflammation. Therefore, BCAA metabolism may serve as a critical link connecting metabolic dysregulation in diabetes with macrophage immunometabolic reprogramming and chronic inflammatory responses. Targeting BCAA metabolism is expected to provide new multi-target intervention strategies for metabolic inflammation in diabetes.