| First Author | Templin AT | Year | 2017 |
| Journal | Diabetes | Volume | 66 |
| Issue | 10 | Pages | 2636-2645 |
| PubMed ID | 28729244 | Mgi Jnum | J:246401 |
| Mgi Id | MGI:5918983 | Doi | 10.2337/db16-1352 |
| Citation | Templin AT, et al. (2017) Apoptosis Repressor With Caspase Recruitment Domain Ameliorates Amyloid-Induced beta-Cell Apoptosis and JNK Pathway Activation. Diabetes 66(10):2636-2645 |
| abstractText | Islet amyloid is present in more than 90% of individuals with type 2 diabetes, where it contributes to beta-cell apoptosis and insufficient insulin secretion. Apoptosis repressor with caspase recruitment domain (ARC) binds and inactivates components of the intrinsic and extrinsic apoptosis pathways and was recently found to be expressed in islet beta-cells. Using a human islet amyloid polypeptide transgenic mouse model of islet amyloidosis, we show ARC knockdown increases amyloid-induced beta-cell apoptosis and loss, while ARC overexpression decreases amyloid-induced apoptosis, thus preserving beta-cells. These effects occurred in the absence of changes in islet amyloid deposition, indicating ARC acts downstream of amyloid formation. Because islet amyloid increases c-Jun N-terminal kinase (JNK) pathway activation, we investigated whether ARC affects JNK signaling in amyloid-forming islets. We found ARC knockdown enhances JNK pathway activation, whereas ARC overexpression reduces JNK, c-Jun phosphorylation, and c-Jun target gene expression (Jun and Tnf). Immunoprecipitation of ARC from mouse islet lysates showed ARC binds JNK, suggesting interaction between JNK and ARC decreases amyloid-induced JNK phosphorylation and downstream signaling. These data indicate that ARC overexpression diminishes amyloid-induced JNK pathway activation and apoptosis in the beta-cell, a strategy that may reduce beta-cell loss in type 2 diabetes. |
