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

Jinyoung Kim,Myung-Shik Lee,Kook Hwan Kim,Eun-Seo Lee,Hyejin Lim,Ji-Won Kim,Jae Hyeon Kim,Sun-Woo Kim,Jin Hee Ahn,Hyongbum Kim,Kyu Yeon Hur,Min Jung Kim,Kun-Ho Yoon,Sung Joo Kim,Kihyoun Park

doi:10.1038/s41467-020-20454-z

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.

Highlights

We have reported that autophagy is crucial for clearance of amyloidogenic human islet amyloid polypeptide (IAPP) oligomer, suggesting that an autophagy enhancer could be a therapeutic modality against human diabetes with amyloid accumulation
Others and we previously reported that human-type IAPP oligomer or amyloid accumulation in transgenic mice expressing human IAPP (hIAPP) or hIAPP knock-in mice in which endogenous murine IAPP gene was replaced by hIAPP markedly increases when β-cell autophagy is deficient, suggesting that autophagy is critical in the clearance of hIAPP oligomer or amyloid[3,4,5]
Since MSL-7 induces the nuclear translocation of TFEB and TFE3 IB: GFP (TFE3), critical regulators of lysosome biogenesis and autophagy gene expression, in pancreatic islet cells or INS-1 insulinoma cells, we studied the role of MiTF/TFE family members in the accelerated clearance of hIAPP oligomer and improved viability of islet cells

Summary

Introduction

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. Protective effects of MSL-7 against hIAPP oligomermediated β-cell death and the development of diabetes are significantly reduced by βcell-specific knockout of Tfeb These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation. We found that MSL-7 improved the glucose tolerance and β-cell function of hIAPP+ mice rendered diabetic by HFD feeding, which was accompanied by reduced accumulation of hIAPP oligomer and islet amyloid These results suggest that an autophagy enhancer acting in a TFEB-dependent manner could have a therapeutic potential against human diabetes characterized by islet amyloid accumulation

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Results

Conclusion