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

Noemí Alejandra Saavedra-Ávila, Upasana Sengupta, Begoña Sánchez, Ester Sala, Laura Haba, Thomas Stratmann, Joan Verdaguer, Dídac Mauricio, Belén Mezquita, Ana Belén Ropero, Ángel Nadal, Conchi Mora

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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 overexpressing 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.

Original languageEnglish (US)
Pages (from-to)E3405-E3414
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number33
DOIs
StatePublished - Aug 19 2014
Externally publishedYes

ASJC Scopus subject areas

  • General

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