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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2014-08-04Author
Saavedra Ávila, Noemí Alejandra
Sengupta, Upasana
Sánchez, Begoña
Sala, Ester
Haba, Laura
Stratmann, Thomas
Mezquita, Bélen
Ropero, Ana Belén
Nadal, Ángel
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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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.