Immune activation induced by dysregulated lipid metabolism in the pathogenesis of type 2 diabetes

Figure 1 Mechanisms of lipid accumulation-induced adipose tissue immune microenvironment disruption and insulin resistance. Mechanisms including: (1) Adipocyte hypertrophy and macrophage activation: Hypertrophied adipocytes release excessive free fatty acids (FFAs), which promote macrophage recruitment and differentiation into adipose tissue macrophages. FFAs activate macrophages via receptors such as Toll-like receptor (TLR) 4 and cluster of differentiation (CD) 36, driving polarization toward the pro-inflammatory M1 phenotype. This leads to the secretion of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6. Additionally, fetuin-A binds to TLR4 and indirectly activates the nuclear factor kappa-B signaling pathway, further enhancing TNF-α and IL-6 production. These cytokines collectively impair insulin signal transduction; (2) Monocyte recruitment and infiltration: FFAs and the chemokine monocyte chemoattractant protein-1 (CCL2) recruit circulating monocytes to adipose tissue via the CCR2 pathway. Upon infiltration, these monocytes differentiate into macrophages, amplifying the inflammatory response; (3) T cell activation and cytokine secretion: Under the influence of FFAs, both CD4⁺ and CD8⁺ T cells become activated and proliferate. They secrete cytokines such as interferon-gamma, which enhance inflammatory responses and promote further macrophage recruitment and activation; and (4) B cell involvement in inflammation: B cells accumulate in adipose tissue, where they contribute to inflammation by activating T cells and secreting pathogenic IgG antibodies and the chemokine CXCL10. These actions exacerbate both local and systemic inflammation, further impairing insulin sensitivity. IL: Interleukin; TNF: Tumor necrosis factor; NF-κB: Nuclear factor kappa-B; TLR: Toll-like receptor; FetA: Fetuin-A; ATM: Adipose tissue macrophage; CD: Cluster of differentiation; FFAs: Free fatty acids; IFN: Interferon; MCP-1: Monocyte chemoattractant protein-1.