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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

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Issue date
2014-08-04
Author
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
Suggested citation
Saavedra Ávila, Noemí Alejandra; Sengupta, Upasana; Sánchez, Begoña; Sala, Ester; Haba, Laura; Stratmann, Thomas; ... Mora Giral, Concepció. (2014) . Cyclin D3 promotes pancreatic beta-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes. PNAS Proceedings of the National Academy of Sciences of the United States of America, 2014, vol. 111, num. 33, p. 3405-3414. https://doi.org/10.1073/pnas.1323236111.
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Abstract
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.
URI
http://hdl.handle.net/10459.1/48044
DOI
https://doi.org/10.1073/pnas.1323236111
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PNAS Proceedings of the National Academy of Sciences of the United States of America, 2014, vol. 111, num. 33, p. 3405-3414
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