| First Author | Jiang X | Year | 2017 |
| Journal | Diabetologia | Volume | 60 |
| Issue | 3 | Pages | 464-474 |
| PubMed ID | 28011992 | Mgi Jnum | J:240104 |
| Mgi Id | MGI:5882432 | Doi | 10.1007/s00125-016-4185-z |
| Citation | Jiang X, et al. (2017) APPL1 prevents pancreatic beta cell death and inflammation by dampening NFkappaB activation in a mouse model of type 1 diabetes. Diabetologia 60(3):464-474 |
| abstractText | AIMS/HYPOTHESIS: Beta cell inflammation and demise is a feature of type 1 diabetes. The insulin-sensitising molecule 'adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1' (APPL1), which contains an NH2-terminal Bin/Amphiphysin/Rvs domain, a central pleckstrin homology domain and a COOH-terminal phosphotyrosine-binding domain, has been shown to modulate inflammatory response in various cell types but its role in regulating beta cell mass and inflammation in type 1 diabetes remains unknown. Thus, we investigated whether APPL1 prevents beta cell apoptosis and inflammation in diabetes. METHODS: Appl1-knockout mice and their wild-type littermates, as well as C57BL/6N mice injected with adeno-associated virus encoding APPL1 or green fluorescent protein, were treated with multiple-low-dose streptozotocin (MLDS) to induce experimental type 1 diabetes. Their glucose metabolism and beta cell function were assessed. The effect of APPL1 deficiency on beta cell function upon exposure to a diabetogenic cytokine cocktail (CKS; consisting of TNF-alpha, IL-1beta and IFN-gamma) was assessed ex vivo. RESULTS: Expression of APPL1 was significantly reduced in pancreatic islets from mouse models of type 1 diabetes or islets treated with CKS. Hyperglycaemia, beta cell loss and insulitis induced by MLDS were exacerbated by genetic deletion of Appl1 but were alleviated by beta cell-specific overexpression of APPL1. APPL1 preserved beta cell mass by reducing beta cell apoptosis upon treatment with MLDS. Mechanistically, APPL1 deficiency potentiate CKS-induced phosphorylation of NFkappaB inhibitor, alpha (IkappaBalpha) and subsequent phosphorylation and transcriptional activation of p65, leading to a dramatic induction of NFkappaB-regulated apoptotic and proinflammatory programs in beta cells. Pharmacological inhibition of NFkappaB or inducible NO synthase (iNOS) largely abrogate the detrimental effects of APPL1 deficiency on beta cell functions. CONCLUSIONS/INTERPRETATION: APPL1 negatively regulates inflammation and apoptosis in pancreatic beta cells by dampening the NFkappaB-iNOS-NO axis, representing a promising target for treating type 1 diabetes. |
