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Cyclin D3 promotes pancreatic beta-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes
Saavedra Ávila, Noemí Alejandra; SenGupta, Upasana; Sánchez, Begoña; Sala, Ester; Haba, Laura; Stratmann, Thomas; Verdaguer Autonell, Joan; Mauricio Puente, Dídac; Mezquita, Bélen; Ropero, Ana Belén; Nadal, Ángel; Mora Giral, Concepció
Type 1 diabetes is an autoimmune condition caused by the lymphocyte-mediated destruction of the insulin-producing β cells in pancreatic islets. We aimed to identify final molecular entities targeted by the autoimmune assault on pancreatic β cells that are causally related to β cell viability. Here, we show that cyclin D3 is targeted by the autoimmune attack on pancreatic β cells in vivo. Cyclin D3 is down-regulated in a dose-dependent manner in β 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 β-cell fitness and viability in the NOD mice. We found that changes in cyclin D3 expression levels in vivo altered the β-cell apoptosis rates, β-cell area homeostasis, and β-cell sensitivity to glucose without affecting β-cell proliferation in the NOD mice. Cyclin D3-deficient NOD mice exhibited exacerbated diabetes and impaired glucose responsiveness; conversely, transgenic NOD mice verexpressing cyclin D3 in β cells exhibited mild diabetes and improved glucose responsiveness. Overexpression of cyclin D3 in β 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 β cells against inflammation-induced apoptosis and confers metabolic fitness to these cells.
2014-08-04
diabetis tipus 1
Autoantígens
autoimmunitat
ratón NOD (non obese diabetic)
(c) Saavedra Ávila, Noemí Alejandra et al., 2014
Article
PNAS
         

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