Liganded thyroid hormone receptor-alpha enhances proliferation of pancreatic beta-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.
Furuya
Fumihiko
F
Third Department of Internal Medicine, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo-shi, Yamanashi 409-3898, Japan.
Shimura
Hiroki
H
Yamashita
Sayaka
S
Endo
Toyoshi
T
Kobayashi
Tetsuro
T
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology*; D008024:Ligands; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D034741:RNA, Small Interfering / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism / Q000502:physiology*
D008024:Ligands; D034741:RNA, Small Interfering; D016160:Retinoblastoma Protein; D037021:Thyroid Hormone Receptors alpha; D019938:Cyclin D1