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An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer
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An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer
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Journal Article
An autophagy enhancer ameliorates diabetes of human IAPP-transgenic mice through clearance of amyloidogenic oligomer
2021
Overview
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.
Islet amyloid polypeptide (IAPP) deposition is associated with islet cell loss in diabetes. Here the authors show that a small molecule autophagy enhancer reduces IAPP accumulation in vitro, and also improves glucose tolerance in
hIAPP
+
mice fed high-fat diet, accompanied by reduced hIAPP accumulation, in vivo.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/19
/ 45/77
/ 45/90
/ 64/60
/ 82/80
/ Amylin
/ Amyloidogenic Proteins - metabolism
/ Animals
/ Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics
/ Diabetes
/ Diabetes Mellitus, Type 2 - metabolism
/ Diet
/ Glucose
/ Humanities and Social Sciences
/ Humans
/ Induced Pluripotent Stem Cells - metabolism
/ Islet Amyloid Polypeptide - genetics
/ Islet Amyloid Polypeptide - metabolism
/ Mice
/ Science
