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

Publicated to:Proceedings Of The National Academy Of Sciences Of The United States Of America. 111 (33): E3405-E3414 - 2014-08-19 111(33), DOI: 10.1073/pnas.1323236111

Authors: Alejandra Saavedra-Avila, Noemi; Sengupta, Upasana; Sanchez, Begona; Sala, Ester; Haba, Laura; Stratmann, Thomas; Verdaguer, Joan; Mauricio, Didac; Mezquita, Belen; Belen Ropero, Ana; Nadal, Angel; Mora, Conchi

Affiliations

Hosp Badalona Germans Trias & Pujol, Badalona 08916, Spain - Author
Inst Biomed Res August Pi & Sunyer, Expt Diabet Lab, Barcelona 08036, Spain - Author
Inst Recerca Biomed Lleida, Lleida 25198, Spain - Author
Univ Barcelona, Fac Biol, Dept Physiol & Immunol, E-08028 Barcelona, Spain - Author
Univ Barcelona, Lab Mol Genet, Dept Physiol 1, Fac Med, E-08036 Barcelona, Spain - Author
Univ Lleida, Immunol Unit, Dept Expt Med, Fac Med, Lleida 25008, Spain - Author
Univ Miguel Hernandez Elche, Diabet & Associated Metab Disorders CIBERDEM, Elche 03202, Spain - Author
Univ Miguel Hernandez Elche, Inst Bioingn, Elche 03202, Spain - Author
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Abstract

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.

Keywords
Good health and well-being

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Proceedings Of The National Academy Of Sciences Of The United States Of America due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2014, it was in position 4/57, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 1.33, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-03, the following number of citations:

  • WoS: 9
  • Scopus: 9
  • Europe PMC: 7
  • Open Alex: 10
  • OpenCitations: 10
Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-05-03:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 29.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 29 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 3.
  • The number of mentions on the social network Facebook: 2 (Altmetric).
  • The number of mentions on the social network X (formerly Twitter): 3 (Altmetric).
Continuing with the social impact of the work, it is important to emphasize that, due to its content, it can be assigned to the area of interest of ODS 3 - Good Health And Well-being, with a probability of 86% according to the mBERT algorithm developed by Aurora University.