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Prolonged glucagon exposure rewires lipid oxidation and drives diabetic kidney disease progression

Author

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  • Xingfeng Liu

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Jingwen Chen

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Shengying Gu

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Yibing Chen

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Ruiping Zhang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Qingce Zang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Ting Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Hanwen Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Dejin Lu

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Shaocong Hou

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Lijuan Kong

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Qian Jiang

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Caiyi Xing

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Wenjia Fan

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Yanjun Wan

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Jiaqi Zhang

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Linyuan Zhu

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Chunxiao Ma

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Qijin Zhao

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Hai Yan

    (REMD Biotherapeutics Inc.)

  • Zeper Abliz

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bing Cui

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

  • Pingping Li

    (Chinese Academy of Medical Sciences and Peking Union Medical College
    Diabetes Research Center of Chinese Academy of Medical Sciences
    CAMS Key Laboratory of Molecular Mechanism and Target Discovery of Metabolic Disorder and Tumorigenesis)

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Tubular abnormalities may precede glomerular pathology and indicate functional progression of DKD. Here, we find glucagon injection exacerbates lipid accumulation and renal injury, in addition to causing morphological changes in proximal tubules, podocytes, and mitochondria in the early phase of DKD in mice. However, the specific knockdown or knockout of Gcgr in renal tubular epithelial cells almost completely halts DKD development. In contrast to the effect of short-term glucagon stimulation, long-term glucagon exposure leads to the reversal of glucagon action (glucagon reversal) in proximal tubular epithelial cells (PTECs), which is characterized by reduced energy production and an increase in lipogenesis through Gcgr-PKA-Creb-mTORC1 pathway. Accordingly, anti-GCGR antibody treatment strongly blocks the pathogenesis of DKD induced by both type 2 and type 1 diabetes. Thus, our results highlight a previously unrecognized role of glucagon/Gcgr signaling in PTEC lipogenesis and DKD.

Suggested Citation

  • Xingfeng Liu & Jingwen Chen & Shengying Gu & Yibing Chen & Ruiping Zhang & Qingce Zang & Ting Li & Hanwen Li & Dejin Lu & Shaocong Hou & Lijuan Kong & Qian Jiang & Caiyi Xing & Wenjia Fan & Yanjun Wan, 2025. "Prolonged glucagon exposure rewires lipid oxidation and drives diabetic kidney disease progression," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63529-5
    DOI: 10.1038/s41467-025-63529-5
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