Failure of the functional pancreatic beta-cell mass to expand in response to 
increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing 
studies indicate that replication of existing beta-cells is important for 
beta-cell proliferation in adult animals. In rat pancreatic beta-cell lines 
(RIN5F), treatment with 100 nM thyroid hormone (triiodothyronine, T(3)) enhances 
cell proliferation. This result suggests that T(3) is required for beta-cell 
proliferation or replication. To identify the role of thyroid hormone receptor 
alpha (TR(alpha)) in the processes of beta-cell growth and cell cycle 
regulation, we constructed a recombinant adenovirus vector, AdTR(alpha). 
Infection with AdTR(alpha) to RIN5F cells increased the expression of cyclin D1 
mRNA and protein. Overexpression of the cyclin D1 protein in 
AdTR(alpha)-infected cells led to activation of the cyclin D1/cyclin-dependent 
kinase/retinoblastoma protein/E2F pathway, along with cell cycle progression and 
cell proliferation following treatment with 100 nM T(3). Conversely, lowering 
cellular cyclin D1 by small interfering RNA knockdown in AdTR(alpha)-infected 
cells led to down-regulation of the cyclin D1/CDK/Rb/E2F pathway and inhibited 
cell proliferation. Furthermore, in immunodeficient mice with 
streptozotocin-induced diabetes, intrapancreatic injection of AdTR(alpha) led to 
the restoration of islet function and to an increase in the beta-cell mass. 
These results support the hypothesis that liganded TR(alpha) plays a critical 
role in beta-cell replication and in expansion of the beta-cell mass during 
postnatal development. Thus, liganded TR(alpha) may be a target for therapeutic 
strategies that can induce the expansion and regeneration of beta-cells.