NOX2-dependent macrophage-β-cell crosstalk exacerbate islet dysfunction in type 2 diabetes.

Lipotoxicity-induced β-cell failure in type 2 diabetes mellitus (T2DM) involves intrinsic damage and inflammatory crosstalk with islet macrophages, but the initiating signals remain undefined. We identify NOX2 as the hub linking metabolic stress to macrophage-dependent β-cell injury. In high-fat diet-fed and Cybb-knockout mice, and in MIN6-RAW264.7 co-cultures, palmitate upregulates NOX2 in β-cells, activating TLR2/NF-κB/NLRP3 signaling and impairing insulin secretion. Damaged β-cells recruit macrophages via chemokines and drive M1 polarization. Activated macrophages release IL-1β and other cytokines, which suppress PDX1 and amplify β-cell apoptosis-a feedforward amplification loop. Genetic Cybb deletion or apocynin treatment disrupted this cycle, preserved insulin secretion, and improved glucose tolerance. We define the NOX2/TLR/NF-κB/NLRP3/IL-1β axis as the mechanistic link between lipotoxicity and paracrine inflammation in β-cell failure, and identify NOX2 as a therapeutic target for preserving islet function in T2DM.