title: Cyclin D3 promotes pancreatic β-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes.
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.
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, 25008 Lleida, Spain;Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain;
authors.forename: Noemí Alejandra
authors.identifier: http://orcid.org/0000-0003-3064-7254
authors.initials: NA
authors.lastname: Saavedra-Ávila
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, 25008 Lleida, Spain;Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain;
authors.forename: Upasana
authors.initials: U
authors.lastname: Sengupta
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, 25008 Lleida, Spain;Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain;
authors.forename: Begoña
authors.initials: B
authors.lastname: Sánchez
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, 25008 Lleida, Spain;Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain;
authors.forename: Ester
authors.initials: E
authors.lastname: Sala
authors.affiliation: Experimental Diabetes Laboratory, Institute for Biomedical Research August Pi i Sunyer, 08036 Barcelona, Spain;
authors.forename: Laura
authors.initials: L
authors.lastname: Haba
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain;
authors.forename: Thomas
authors.initials: T
authors.lastname: Stratmann
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, 25008 Lleida, Spain;Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain;
authors.forename: Joan
authors.initials: J
authors.lastname: Verdaguer
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, 25008 Lleida, Spain;Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain;Endocrinology and Nutrition, Hospital Germans Trias i Pujol, 08916 Badalona, Spain;
authors.forename: Dídac
authors.initials: D
authors.lastname: Mauricio
authors.affiliation: Laboratory of Molecular Genetics, Department of Physiology I, Faculty of Medicine, Campus Casanova, University of Barcelona, 08036 Barcelona, Spain;
authors.forename: Belén
authors.identifier: http://orcid.org/0000-0003-3180-3255
authors.initials: B
authors.lastname: Mezquita
authors.affiliation: Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, 03202 Elche, Spain; and.
authors.forename: Ana Belén
authors.initials: AB
authors.lastname: Ropero
authors.affiliation: Instituto de Bioingeniería, Universidad Miguel Hernández de Elche, 03202 Elche, Spain; andDiabetes and Associated Metabolic Disorders CIBERDEM, Universidad Miguel Hernández de Elche, 03202 Elche, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Nadal
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida, 25008 Lleida, Spain;Institut de Recerca Biomèdica de Lleida, 25198 Lleida, Spain; Conchi.mora@mex.udl.cat.
authors.forename: Conchi
authors.initials: C
authors.lastname: Mora
mesh_terms: D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D056743:Cyclin D3 / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD
chemical_list: D056743:Cyclin D3; D016207:Cytokines
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