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

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.

Automated summary

The study demonstrates that the autophagy enhancer MSL-7 reduces the accumulation of human IAPP oligomers and diminishes oligomer-mediated apoptosis of beta-cells, leading to improved glucose tolerance and beta-cell function. These protective effects against beta-cell death and diabetes development suggest the therapeutic potential of autophagy enhancers in human diabetes with islet amyloid accumulation.