Cyclin D3 promotes pancreatic ß-cell fitness and viability in a cell cycle-independent manner and is targeted in autoimmune diabetes.
Proc Natl Acad Sci U S A
; 111(33): E3405-14, 2014 Aug 19.
Article
in En
| MEDLINE
| ID: mdl-25092329
ABSTRACT
Type 1 diabetes is an autoimmune condition caused by the lymphocyte-mediated destruction of the insulin-producing ß cells in pancreatic islets. We aimed to identify final molecular entities targeted by the autoimmune assault on pancreatic ß cells that are causally related to ß cell viability. Here, we show that cyclin D3 is targeted by the autoimmune attack on pancreatic ß cells in vivo. Cyclin D3 is down-regulated in a dose-dependent manner in ß 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 ß-cell fitness and viability in the NOD mice. We found that changes in cyclin D3 expression levels in vivo altered the ß-cell apoptosis rates, ß-cell area homeostasis, and ß-cell sensitivity to glucose without affecting ß-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 ß cells exhibited mild diabetes and improved glucose responsiveness. Overexpression of cyclin D3 in ß 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 ß cells against inflammation-induced apoptosis and confers metabolic fitness to these cells.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Cell Cycle
/
Islets of Langerhans
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Diabetes Mellitus, Experimental
/
Diabetes Mellitus, Type 1
/
Cyclin D3
Limits:
Animals
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2014
Document type:
Article