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

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 ?-cells (hiPSC-?-cells) and diminishes oligomer-mediated apoptosis of ?-cells. Protective effects of MSL-7 against hIAPP oligomer accumulation and hIAPP oligomer-mediated ?-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 ?-cell function of hIAPP⁺ mice on high-fat diet, accompanied by reduced hIAPP oligomer/amyloid accumulation and ?-cell apoptosis. Protective effects of MSL-7 against hIAPP oligomer-mediated ?-cell death and the development of diabetes are also significantly reduced by ?-cell-specific knockout of Tfeb. These results suggest that an autophagy enhancer could have therapeutic potential against human diabetes characterized by islet amyloid accumulation.

SUBMITTER: Kim J 

PROVIDER: S-EPMC7794419 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature