| Title |
APPL1 prevents pancreatic beta cell death and inflammation by dampening NFκB activation in a mouse model of type 1 diabetes
|
|---|---|
| Published in |
Diabetologia, December 2016
|
| DOI | 10.1007/s00125-016-4185-z |
| Pubmed ID | |
| Authors |
Xue Jiang, Yawen Zhou, Kelvin K. L. Wu, Zhanrui Chen, Aimin Xu, Kenneth K. Y. Cheng |
| Abstract |
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. 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-α, IL-1β and IFN-γ) was assessed ex vivo. 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 NFκB inhibitor, α (IκBα) and subsequent phosphorylation and transcriptional activation of p65, leading to a dramatic induction of NFκB-regulated apoptotic and proinflammatory programs in beta cells. Pharmacological inhibition of NFκB or inducible NO synthase (iNOS) largely abrogate the detrimental effects of APPL1 deficiency on beta cell functions. APPL1 negatively regulates inflammation and apoptosis in pancreatic beta cells by dampening the NFκB-iNOS-NO axis, representing a promising target for treating type 1 diabetes. |
X Demographics
The data shown below were collected from the profiles of 6 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| United Kingdom | 1 | 17% |
| United Arab Emirates | 1 | 17% |
| Germany | 1 | 17% |
| United States | 1 | 17% |
| Unknown | 2 | 33% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 4 | 67% |
| Practitioners (doctors, other healthcare professionals) | 1 | 17% |
| Science communicators (journalists, bloggers, editors) | 1 | 17% |
Mendeley readers
The data shown below were compiled from readership statistics for 21 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Unknown | 21 | 100% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Bachelor | 9 | 43% |
| Researcher | 3 | 14% |
| Student > Ph. D. Student | 3 | 14% |
| Student > Doctoral Student | 2 | 10% |
| Other | 1 | 5% |
| Other | 2 | 10% |
| Unknown | 1 | 5% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 7 | 33% |
| Medicine and Dentistry | 7 | 33% |
| Agricultural and Biological Sciences | 4 | 19% |
| Sports and Recreations | 1 | 5% |
| Nursing and Health Professions | 1 | 5% |
| Other | 0 | 0% |
| Unknown | 1 | 5% |
Attention Score in Context
This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 02 March 2017.
All research outputs
#7,407,362
of 22,931,367 outputs
Outputs from Diabetologia
#2,826
of 5,056 outputs
Outputs of similar age
#138,321
of 420,129 outputs
Outputs of similar age from Diabetologia
#57
of 65 outputs
Altmetric has tracked 22,931,367 research outputs across all sources so far. This one has received more attention than most of these and is in the 67th percentile.
So far Altmetric has tracked 5,056 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 22.6. This one is in the 44th percentile – i.e., 44% of its peers scored the same or lower than it.
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We're also able to compare this research output to 65 others from the same source and published within six weeks on either side of this one. This one is in the 12th percentile – i.e., 12% of its contemporaries scored the same or lower than it.