Cyclin D3 promotes pancreatic ?-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes.

ABSTRACT: Type 1 diabetes is an autoimmune condition caused by the lymphocyte-mediated destruction of the insulin-producing ? cells in pancreatic islets. We aimed to identify final molecular entities targeted by the autoimmune assault on pancreatic ? cells that are causally related to ? cell viability. Here, we show that cyclin D3 is targeted by the autoimmune attack on pancreatic ? cells in vivo. Cyclin D3 is down-regulated in a dose-dependent manner in ? 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 ?-cell fitness and viability in the NOD mice. We found that changes in cyclin D3 expression levels in vivo altered the ?-cell apoptosis rates, ?-cell area homeostasis, and ?-cell sensitivity to glucose without affecting ?-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 ? cells exhibited mild diabetes and improved glucose responsiveness. Overexpression of cyclin D3 in ? 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 ? cells against inflammation-induced apoptosis and confers metabolic fitness to these cells.

SUBMITTER: Saavedra-Avila NA 

PROVIDER: S-EPMC4143060 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature