Authors
Sihang Fang, Mingjun Jiang, Dizhi Liu, Danni Gao, Liwei Gao, Juan Jiao, Hongye Zhao, Lei Tang, Yan Zhou, Huiping Yuan
Published in
Biochimica et biophysica acta. Molecular basis of disease. Pages 168392. Aug 01, 2026. Epub Aug 01, 2026.
Abstract
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.
PMID:
42542192
Bibliographic data and abstract were imported from PubMed on 02 Aug 2026.
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