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FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes

Author

Listed:
  • Xinyi Chen

    (Department of Pharmacology)

  • Jingchen Shao

    (Department of Pharmacology)

  • Isabell Brandenburger

    (Department of Pharmacology)

  • Weikun Qian

    (Pancreas Center of Xi’an Jiaotong University)

  • Lisa Hahnefeld

    (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD)
    Faculty of Medicine)

  • Rémy Bonnavion

    (Department of Pharmacology)

  • Haaglim Cho

    (Department of Pharmacology)

  • ShengPeng Wang

    (The First Affiliated Hospital of Xi’an Jiaotong University. Xi’an)

  • Juan Hidalgo

    (Autonomous University of Barcelona)

  • Nina Wettschureck

    (Department of Pharmacology
    Goethe University Frankfurt
    Excellence Cluster Cardiopulmonary Institute (CPI)
    partner site Frankfurt/Rhine-Main)

  • Gerd Geisslinger

    (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD)
    Faculty of Medicine)

  • Robert Gurke

    (Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP) and Fraunhofer Cluster of Excellence for Immune Mediated Diseases (CIMD)
    Faculty of Medicine)

  • Zheng Wang

    (Pancreas Center of Xi’an Jiaotong University)

  • Stefan Offermanns

    (Department of Pharmacology
    The First Affiliated Hospital of Xi’an Jiaotong University. Xi’an
    Goethe University Frankfurt
    Excellence Cluster Cardiopulmonary Institute (CPI))

Abstract

The function of islet macrophages is poorly understood. They promote glucose-stimulated insulin secretion (GSIS) in lean mice, however, the underlying mechanism has remained unclear. We show that activation of the free fatty acid receptor FFAR4 on islet macrophages leads to interleukin-6 (IL-6) release and that IL-6 promotes β-cell function. This mechanism is required for GSIS in lean male mice, but does not function anymore in islets from people with obesity and obese type 2 diabetic male mice. In islets from obese mice, FFAR4 downstream signaling in macrophages is strongly reduced, resulting in impaired FFAR4-mediated IL-6 release. However, IL-6 treatment can still improve GSIS in islets from people with obesity and obese type 2 diabetic mice. These data show that a defect in FFAR4-mediated macrophage activation contributes to reduced GSIS in type 2 diabetes and suggest that reactivating islet macrophage FFAR4 and promoting or mimicking IL-6 release from islet macrophages improves GSIS in type 2 diabetes.

Suggested Citation

  • Xinyi Chen & Jingchen Shao & Isabell Brandenburger & Weikun Qian & Lisa Hahnefeld & Rémy Bonnavion & Haaglim Cho & ShengPeng Wang & Juan Hidalgo & Nina Wettschureck & Gerd Geisslinger & Robert Gurke &, 2025. "FFAR4-mediated IL-6 release from islet macrophages promotes insulin secretion and is compromised in type-2 diabetes," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58706-5
    DOI: 10.1038/s41467-025-58706-5
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