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

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, Ji-Won Kim and Myung-Shik Lee ()
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Jinyoung Kim: Yonsei University College of Medicine
Kihyoun Park: Yonsei University College of Medicine
Min Jung Kim: The Catholic University of Korea
Hyejin Lim: Yonsei University College of Medicine
Kook Hwan Kim: Yonsei University College of Medicine
Sun-Woo Kim: 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
Kyu Yeon Hur: Sungkyunkwan University School of Medicine
Jae Hyeon Kim: 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

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-020-20454-z

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