[초청강연] Autophagy enhancer ameliorates human-type diabetes characterized by islet amyloid deposition

Islet amyloid deposition is observed in over 90% of human diabetic patients but not in murine
diabetes, due to differences in the amino acid sequences of islet amyloid polypeptide (IAPP).
We previously reported that autophagy is crucial in the clearance of amyloidogenic human
IAPP (hIAPP) oligomer and suggested that autophagy enhancer could be a therapeutic
modality against human-type diabetes characterized by islet amyloid accumulation. Here, we
show that a recently identified autophagy enhancer (MSL-7) reduced simian IAPP (sIAPP)
and hIAPP oligomer accumulation in primary monkey islet cells and induced pluripotent
stem cell-derived human beta cells, respectively, together with diminution of oligomer-
mediated apoptosis of beta cells. Protective effects of MSL-7 against hIAPP oligomer
accumulation and hIAPP oligomer-mediated beta cell death in vitro were significantly
reduced in cells with targeted disruption of MiTF/TFE family members such as Tfeb or Tfe3.
MSL-7 improved glucose tolerance and beta cell function of hIAPP + mice on high-fat diet in
vivo, 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 in vivo were also significantly reduced by beta cell-specific
knockout of Tfeb. Beta cell-specific Tfeb knockout also impaired adaptive mitophagy in
response to metabolic stress, suggesting the role of beta cell Tfeb in the maintenance of
mitochondrial function. These results suggest that autophagy enhancer could have therapeutic
potential against human diabetes characterized by islet amyloid accumulation. TFEB
activators might have therapeutic potential against Alzheimer’s disease by clearing brain
amyloid.