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

Figure 3 Lipid overload drives innate-adaptive immune imbalance and promotes hepatic insulin resistance. High-fat diet-derived exosomes and pathogen-associated molecular patterns are recognized through cluster of differentiation (CD) 36-mediated uptake and Toll-like receptor 4/myeloid differentiation protein 2 signaling, respectively, leading to Kupffer cell (KC) activation and initiation of nuclear factor kappa-B priming. Under the influence of Notch/immunoglobulin kappa J region-mediated lineage commitment, monocyte-derived macrophages differentiate toward a triggering receptor expressed on myeloid cells 2 lipid-associated macrophage phenotype, whereas the liver X receptor alpha-complement receptor of the immunoglobulin family-T-cell immunoglobulin and mucin domain-containing protein 4 axis supports the maintenance of homeostatic KC identity. Pro-inflammatory stimuli facilitate NLRP3 inflammasome assembly and caspase-1 activation, resulting in interleukin (IL)-1β maturation and secretion, along with increased production of tumor necrosis factor-α and IL-1β. The CD47-signal regulatory protein α checkpoint serves to modulate phagocytic activity and prevent excessive clearance. These inflammatory factors collectively inhibit the hepatocyte insulin signaling cascade, spanning from the insulin receptor to insulin receptor substrate-2, phosphatidylinositol 3-kinase, and protein kinase B, thereby promoting insulin resistance. Simultaneously, shifts in the cytokine milieu favor T-cell differentiation away from regulatory T cells/helper T (Th) 22 subsets toward Th1/Th17 dominance, characterized by elevated interferon-gamma and IL-17 and reduced IL-10 and IL-22, which further exacerbates hepatic insulin resistance and inflammation. HFD: High-fat diet; EV: Extracellular vesicle; IRS: Insulin receptor substrate; PI3K: Phosphatidylinositol 3-kinase; AKT: Protein kinase B; CD: Cluster of differentiation; TLR: Toll-like receptor; MD2: Myeloid differentiation protein 2; SIRPα: Signal regulatory protein α; NF-κB: Nuclear factor kappa-B; PAMP: Pathogen-associated molecular patterns; LXRα-CRIg-TIM4: Liver X receptor alpha-complement receptor of the immunoglobulin family-T-cell immunoglobulin and mucin domain-containing protein 4; RBPJ: Immunoglobulin kappa J region; MoMF: Monocyte-derived macrophage; TREM: Triggering receptor expressed on myeloid cells; LAM: Lipid-associated macrophage; IL: Interleukin; TNF: Tumor necrosis factor; IFN: Interferon; Treg: Regulatory T cell; Th: Helper T.