A small molecule improves diabetes in mice expressing human islet amyloid polypeptide

Abstract

In recent years, the number of studies on islet and beta cell autophagy have substantially increased due to growing interest in the role of autophagy in maintaining cellular homeostasis in diabetes. In type 2 diabetes, human islet amyloid polypeptide (hIAPP) aggregates to form higher structure oligomers and fibrils that are toxic to beta cells and induce islet inflammation. The primary mechanism of oligomer and fibril clearance in beta cells is through the autophagic pathway, a process that is impaired in type 2 diabetes. Thus, toxic oligomeric and fibrillar forms of hIAPP accumulate in type 2 diabetic islets. Recently, Kim et al. characterized the ability of a small molecule autophagy enhancer, MSL-7, to clear hIAPP oligomers in mice expressing hIAPP. Herein, we outline the primary findings of the study, limitations, and future directions to further investigate the therapeutic potential of autophagy enhancers to treat diabetes.

Keywords: Islets; amylin; amyloid; autophagy; beta cells; islet amyloid polypeptide; small molecule.

Graphical abstract

Figure 1.

Caption: Mechanism of action of the small molecule autophagy enhancer, MSL-7. MSL-7 enters cells from the extracellular environment to activate the phosphatase calcineurin A in the cytoplasm. Calcineurin A dephosphorylates two regulators of autophagy and lysosomal biogenesis, the transcription factors TFEB and TFE3. TFEB and TFE3 translocate to the nucleus and activate the expression of autophagy and lysosomal genes. This results in enhanced autophagolysosome activity. Toxic human IAPP oligomers and fibrils are degraded by enzymes in the autophagolysosomes. Figure of a cell. A pink shape representing the small molecule MSL-7 enters the cell from the extracellular environment shown with an arrow. The pink shape representing MSL-7 is shown beside another turquoise shape representing calcineurin A to depict calcineurin A activation. An arrow then points to a gray oval representing the transcription factors TFEB and TFE3, which is then shown to enter the nucleus of the cell by another arrow. In the nucleus is the gray oval shape representing the transcription factor on a black line with a short arrow pointing to the right to depict transcription of autophagy and lysosomal genes. Nuclear mRNAs are depicted with red wavy lines. An arrow points to autophagolysosomes in the cytoplasm. One autophagolysosome is enlarged to the right of the cell to show the contents. The enlarged autophagolysosome shows long blue wavy lines clustered together representing human IAPP oligomers and fibrils, and smaller blue lines representing degraded human IAPP oligomers and fibrils.