| First Author | Nishimura Y | Year | 2022 |
| Journal | Acta Diabetol | Volume | 59 |
| Issue | 10 | Pages | 1275-1286 |
| PubMed ID | 35829914 | Mgi Jnum | J:329238 |
| Mgi Id | MGI:7341929 | Doi | 10.1007/s00592-022-01930-y |
| Citation | Nishimura Y, et al. (2022) XAF1 overexpression exacerbates diabetes by promoting pancreatic beta-cell apoptosis. Acta Diabetol 59(10):1275-1286 |
| abstractText | AIMS: Pancreatic beta-cell apoptosis may be involved in the onset and progression of type 2 diabetes mellitus, although its mechanism remains unclear. We previously demonstrated that macrophage-derived interferon (IFN) beta induced X-linked inhibitor of apoptosis-associated factor 1 (XAF1) expression in beta-cells and accelerated beta-cell apoptosis in vitro. Here, we explored the effects of XAF1 on beta-cell function and progression of diabetes in vivo. METHODS: Pancreatic beta-cell-selective XAF1 overexpressing (Xaf1 Tg) mice were generated. Xaf1 Tg mice and their wild-type (WT) littermates were fed either a normal diet or a 40% or 60% high-fat diet (HFD). The effects of beta-cell XAF1 on beta-cell apoptosis and exacerbation of diabetes were investigated. RESULTS: Palmitic acid induced IFNbeta expression in macrophages, and HFD intake promoted macrophage infiltration in pancreatic islets, both of which cooperatively upregulated XAF1 expression in mouse islets. Furthermore, HFD-fed Xaf1 Tg mice demonstrated increased beta-cell apoptosis, lowered insulin expression, and impaired glucose tolerance compared with WT mice fed the same diet. These effects were more pronounced in the 60%HFD group than in the 40%HFD group. CONCLUSIONS: Pancreatic beta-cell XAF1 expression was enhanced via HFD-induced, macrophage-derived IFNbeta, which promoted beta-cell apoptosis and led to a reduction in insulin secretion and progression of diabetes. To our knowledge, this is the first report to demonstrate an association between pancreatic beta-cell XAF1 overexpression and exacerbation of diabetes, thus providing insight into the mechanism of beta-cell mass reduction in diabetes. |
