| First Author | Saavedra-Ávila NA | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 33 | Pages | E3405-14 |
| PubMed ID | 25092329 | Mgi Jnum | J:213923 |
| Mgi Id | MGI:5586905 | Doi | 10.1073/pnas.1323236111 |
| Citation | Saavedra-Avila NA, et al. (2014) Cyclin D3 promotes pancreatic beta-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes. Proc Natl Acad Sci U S A 111(33):E3405-14 |
| abstractText | Type 1 diabetes is an autoimmune condition caused by the lymphocyte-mediated destruction of the insulin-producing beta cells in pancreatic islets. We aimed to identify final molecular entities targeted by the autoimmune assault on pancreatic beta cells that are causally related to beta cell viability. Here, we show that cyclin D3 is targeted by the autoimmune attack on pancreatic beta cells in vivo. Cyclin D3 is down-regulated in a dose-dependent manner in beta cells by leukocyte infiltration into the islets of the nonobese diabetic (NOD) type 1 diabetes-prone mouse model. Furthermore, we established a direct in vivo causal link between cyclin D3 expression levels and beta-cell fitness and viability in the NOD mice. We found that changes in cyclin D3 expression levels in vivo altered the beta-cell apoptosis rates, beta-cell area homeostasis, and beta-cell sensitivity to glucose without affecting beta-cell proliferation in the NOD mice. Cyclin D3-deficient NOD mice exhibited exacerbated diabetes and impaired glucose responsiveness; conversely, transgenic NOD mice overexpressing cyclin D3 in beta cells exhibited mild diabetes and improved glucose responsiveness. Overexpression of cyclin D3 in beta cells of cyclin D3-deficient mice rescued them from the exacerbated diabetes observed in transgene-negative littermates. Moreover, cyclin D3 overexpression protected the NOD-derived insulinoma NIT-1 cell line from cytokine-induced apoptosis. Here, for the first time to our knowledge, cyclin D3 is identified as a key molecule targeted by autoimmunity that plays a nonredundant, protective, and cell cycle-independent role in beta cells against inflammation-induced apoptosis and confers metabolic fitness to these cells. |
