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An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer

Author

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  • Jinyoung Kim

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Kihyoun Park

    (Yonsei University College of Medicine
    Sungkyunkwan University School of Medicine)

  • Min Jung Kim

    (The Catholic University of Korea)

  • Hyejin Lim

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Kook Hwan Kim

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Sun-Woo Kim

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

  • Eun-Seo Lee

    (Yonsei University College of Medicine)

  • Hyongbum (Henry) Kim

    (Yonsei University College of Medicine)

  • Sung Joo Kim

    (Sungkyunkwan University School of Medicine
    Sungkyunkwan University School of Medicine
    Sungkyunkwan University School of Medicine)

  • Kyu Yeon Hur

    (Sungkyunkwan University School of Medicine
    Samsung Medical Center, Sungkyunkwan University School of Medicine)

  • Jae Hyeon Kim

    (Sungkyunkwan University School of Medicine
    Samsung Medical Center, Sungkyunkwan University School of Medicine)

  • Jin Hee Ahn

    (Gwangju Institute of Science and Technology)

  • Kun-Ho Yoon

    (The Catholic University of Korea)

  • Ji-Won Kim

    (The Catholic University of Korea)

  • Myung-Shik Lee

    (Yonsei University College of Medicine
    Yonsei University College of Medicine)

Abstract

We have reported that autophagy is crucial for clearance of amyloidogenic human IAPP (hIAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation. Here, we show that a recently identified autophagy enhancer (MSL-7) reduces hIAPP oligomer accumulation in human induced pluripotent stem cell-derived β-cells (hiPSC-β-cells) and diminishes oligomer-mediated apoptosis of β-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated β-cell death are significantly reduced in cells with knockout of MiTF/TFE family members such as Tfeb or Tfe3. MSL-7 improves glucose tolerance and β-cell function of hIAPP+ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and β-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated β-cell death and the development of diabetes are also significantly reduced by β-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

Suggested Citation

  • Jinyoung Kim & Kihyoun Park & Min Jung Kim & Hyejin Lim & Kook Hwan Kim & Sun-Woo Kim & Eun-Seo Lee & Hyongbum (Henry) Kim & Sung Joo Kim & Kyu Yeon Hur & Jae Hyeon Kim & Jin Hee Ahn & Kun-Ho Yoon & J, 2021. "An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20454-z
    DOI: 10.1038/s41467-020-20454-z
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    Cited by:

    1. Kihyoun Park & Hyejin Lim & Jinyoung Kim & Yeseong Hwang & Yu Seol Lee & Soo Han Bae & Hyeongseok Kim & Hail Kim & Shin-Wook Kang & Joo Young Kim & Myung-Shik Lee, 2022. "Lysosomal Ca2+-mediated TFEB activation modulates mitophagy and functional adaptation of pancreatic β-cells to metabolic stress," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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