An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer.
Jinyoung KimKihyoun ParkMin Jung KimHyejin LimKook Hwan KimSun-Woo KimEun-Seo LeeHyongbum Henry KimSung Joo KimKyu Yeon HurJae Hyeon KimJin Hee AhnKun-Ho YoonJi-Won KimMyung-Shik LeePublished in: Nature communications (2021)
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.
Keyphrases
- cell death
- cell cycle arrest
- induced apoptosis
- endothelial cells
- endoplasmic reticulum stress
- type diabetes
- high fat diet
- cardiovascular disease
- oxidative stress
- signaling pathway
- induced pluripotent stem cells
- pluripotent stem cells
- transcription factor
- high glucose
- binding protein
- insulin resistance
- glycemic control
- skeletal muscle
- pi k akt
- diabetic rats
- single cell