한빛사논문
Jinyoung Kim1,2, Kihyoun Park1,3, Min Jung Kim4, Hyejin Lim1,2, Kook Hwan Kim1,2, Sun-Woo Kim1,2, Eun-Seo Lee5, Hyongbum (Henry) Kim5, Sung Joo Kim3,6,7, Kyu Yeon Hur3,8, Jae Hyeon Kim3,8, Jin Hee Ahn9, Kun-Ho Yoon4, Ji-Won Kim4 & Myung-Shik Lee1,2,*
1Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
2Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
3Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University School of Medicine, Seoul, Korea.
4Department of Endocrinology and Metabolism, College of Medicine, The Catholic University of Korea, Seoul, Korea.
5Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea.
6Transplantation Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
7Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, Korea.
8Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
9Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju, Korea.
*Corresponding author
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.
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