Maintenance of hepatic nuclear factor 6 in postnatal islets impairs terminal differentiation and function of beta-cells.


Autoria(s): Tweedie E.; Artner I.; Crawford L.; Poffenberger G.; Thorens B.; Stein R.; Powers A.C.; Gannon M.
Data(s)

2006

Resumo

The Onecut homeodomain transcription factor hepatic nuclear factor 6 (Hnf6) is necessary for proper development of islet beta-cells. Hnf6 is initially expressed throughout the pancreatic epithelium but is downregulated in endocrine cells at late gestation and is not expressed in postnatal islets. Transgenic mice in which Hnf6 expression is maintained in postnatal islets (pdx1(PB)Hnf6) show overt diabetes and impaired glucose-stimulated insulin secretion (GSIS) at weaning. We now define the mechanism whereby maintenance of Hnf6 expression postnatally leads to beta-cell dysfunction. We provide evidence that continued expression of Hnf6 impairs GSIS by altering insulin granule biosynthesis, resulting in a reduced response to secretagogues. Sustained expression of Hnf6 also results in downregulation of the beta-cell-specific transcription factor MafA and a decrease in total pancreatic insulin. These results suggest that downregulation of Hnf6 expression in beta-cells during development is essential to achieve a mature, glucose-responsive beta-cell.

Identificador

http://serval.unil.ch/?id=serval:BIB_17F1B0E4FB6D

isbn:0012-1797

pmid:17130469

doi:10.2337/db06-0090

isiid:000242446800008

Idioma(s)

en

Fonte

Diabetes, vol. 55, no. 12, pp. 3264-3270

Palavras-Chave #Animals; Cell Differentiation; Gene Expression Regulation, Developmental; Glucose; Glucose Transporter Type 2; Hepatocyte Nuclear Factor 6; Homeodomain Proteins; Homeostasis; Insulin; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Transgenic; Trans-Activators
Tipo

info:eu-repo/semantics/article

article