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