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 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.

Insulin Resistance and Diabetes Mellitus in Alzheimer’s Disease

“…On the other hand, autophagy is the main mechanism by which human islet amyloid polypeptide (hIAPP) is degraded, a polypeptide whose accumulation in β cells produces cellular toxicity [ 193 , 194 ]. Recently, the use of autophagy inducers has been shown to improve the metabolic profile of hIAPP-overexpressing mice, by reducing the accumulation of oligomers of IAPP [ 195 ].…”

Mechanisms of Beta-Cell Apoptosis in Type 2 Diabetes-Prone Situations and Potential Protection by GLP-1-Based Therapies

“…Consequently, the alteration in lysosomal degradation impairs the clearance of damaged mitochondria through mitophagy [ 50 ], inducing oxidative stress and further exacerbating beta-cell ER stress and apoptosis. In addition, the implication of the autophagy in h-IAPP clearance itself shown in isolated human islets and in transgenic mouse models [ 51 , 52 , 53 , 54 ] contributes to a vicious cycle whereby IAPP reduces lysosomal degradation, which further promotes IAPP overload and toxicity. Further providing evidence of such deleterious mechanism in vivo, a recent article reveals that an autophagy enhancer ameliorated diabetes of h-IAPP transgenic mice through clearance of amyloidogenic oligomers [ 52 ].…”

“…In addition, the implication of the autophagy in h-IAPP clearance itself shown in isolated human islets and in transgenic mouse models [ 51 , 52 , 53 , 54 ] contributes to a vicious cycle whereby IAPP reduces lysosomal degradation, which further promotes IAPP overload and toxicity. Further providing evidence of such deleterious mechanism in vivo, a recent article reveals that an autophagy enhancer ameliorated diabetes of h-IAPP transgenic mice through clearance of amyloidogenic oligomers [ 52 ]. The potential involvement of autophagy deficits in the decline of beta-cell mass in human T2D has been suggested by the accumulation of autophagic vacuoles [ 55 ] and the increased levels of p62, a marker for lysosomal degradation defects, in beta-cells of T2D human islets [ 37 , 53 , 56 ].…”

The Amyloid Forming Peptides Islet Amyloid Polypeptide and Amyloid β Interact at the Molecular Level

“…The data presented as BiFC(+)/BiFC(−) shows no difference between the vector combinations (Figure 5A). The accumulation of intracellular protein aggregates has been shown to activate autophagy [29,30]. To investigate if autophagy was activated by BiFC expression, transfected cells were cultured in the presence of the autophagy inhibitor 3-methyladenine (3-MA) and the autophagy inducer rapamycin.…”