Liganded Thyroid Hormone Receptor-α Enhances Proliferation of Pancreatic β-Cells

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.