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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  ;  Myung-Shik Lee 
 NATURE COMMUNICATIONS, Vol.12(1) : 183, 2021-01 
Journal Title
Issue Date
Amyloid / metabolism* ; Amyloidogenic Proteins / metabolism* ; Animals ; Apoptosis / physiology ; Autophagy / physiology* ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics ; Diabetes Mellitus, Type 2 / metabolism* ; Gene Knockout Techniques ; Humans ; Induced Pluripotent Stem Cells / metabolism ; Insulin-Secreting Cells ; Islet Amyloid Polypeptide / genetics* ; Islet Amyloid Polypeptide / metabolism* ; Macroautophagy / physiology ; Mice ; Mice, Transgenic
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Jinyoung(김진영) ORCID logo https://orcid.org/0000-0002-3810-8549
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
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