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UCP2 inhibition eliminates pancreatic β cell autoinflammation in T2DM with islet-mitochondrial sequential targeting nanomedicines

Author

Listed:
  • Zerun Liu

    (Central South University
    Central South University)

  • Wensheng Chen

    (Central South University
    Central South University)

  • Jinping Zhang

    (Central South University
    Central South University)

  • Ting Huang

    (Central South University
    Central South University)

  • Ying Hong

    (Central South University
    Central South University)

  • Tianjiao Zhao

    (Central South University
    Central South University)

  • Min Liu

    (Central South University
    Central South University)

  • Qiaohui Chen

    (Central South University
    Central South University)

  • Yongqi Yang

    (Central South University
    Central South University)

  • Shuya Wang

    (Central South University
    Central South University)

  • Jue Wang

    (Central South University
    Central South University)

  • Xiaohong Ying

    (Central South University
    Central South University)

  • Yiming Li

    (Central South University)

  • Qiong Huang

    (Central South University
    Central South University)

  • Kelong Ai

    (Central South University
    Central South University
    Central South University)

Abstract

Pancreatic β-cell dysfunction and mass loss are core pathologies of type 2 diabetes mellitus (T2DM), which are closely related to intense autoinflammation. However, the molecular mechanisms regulating β-cell autoinflammation remain unclear. Here, we show that STING is significantly elevated in T2DM β cells. We also clarify the key role of uncoupling protein 2 (UCP2), and reveal that interleukin-1β (IL-1β) drives β cells to produce autoinflammation through the UCP2/mtDNA/STING axis in T2DM. To inhibit UCP2 activity in vivo, we design a tailored nanomedicine, Mito-G, with sequential targeting from islets to β-cell mitochondria. Mito-G is a negatively charged ultra-small nanomedicine synthesized by polymerization of genipin (a potent UCP2 inhibitor) and glycine. It can specifically reach β cells and have a natural mitochondrial targeting. In this work, Mito-G effectively eliminates β-cell auto-inflammation by specifically inhibiting β-cell UCP2 activity in vivo, providing a paradigm for targeting autoinflammation of β cells to treat T2DM.

Suggested Citation

  • Zerun Liu & Wensheng Chen & Jinping Zhang & Ting Huang & Ying Hong & Tianjiao Zhao & Min Liu & Qiaohui Chen & Yongqi Yang & Shuya Wang & Jue Wang & Xiaohong Ying & Yiming Li & Qiong Huang & Kelong Ai, 2025. "UCP2 inhibition eliminates pancreatic β cell autoinflammation in T2DM with islet-mitochondrial sequential targeting nanomedicines," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61883-y
    DOI: 10.1038/s41467-025-61883-y
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    References listed on IDEAS

    as
    1. Joakim Lehrstrand & Wayne I. L. Davies & Max Hahn & Olle Korsgren & Tomas Alanentalo & Ulf Ahlgren, 2024. "Illuminating the complete ß-cell mass of the human pancreas- signifying a new view on the islets of Langerhans," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
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