Cyclin D3 promotes pancreatic [Beta]-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes

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....

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Published in:Proceedings of the National Academy of Sciences - PNAS 2014-08, Vol.111 (33), p.E3405
Main Authors: Saavedra-Ávila, Noemí Alejandra, Sengupta, Upasana, Sánchez, Begoña, Sala, Ester, Haba, Laura, Stratmann, Thomas, Verdaguer, Joan, Mauricio, Dídac, Mezquita, Belén, Ropero, Ana Belén, Nadal, Ángel, Mora, Conchi
Format: Article
Language:English
Subjects:
Cellular biology
Diabetes
Immunology
Molecular biology
Online Access:Get full text
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Summary: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. (ProQuest: ... denotes formulae/symbols omitted.)
ISSN:0027-8424
1091-6490