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Diabetes. 2010 Jun;59(6):1435-44. doi: 10.2337/db09-1295. Epub 2010 Mar 18.

Ectopic expression of E2F1 stimulates beta-cell proliferation and function.

Author information

1
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.

Abstract

OBJECTIVE:

Generating functional beta-cells by inducing their proliferation may provide new perspectives for cell therapy in diabetes. Transcription factor E2F1 controls G(1)- to S-phase transition during the cycling of many cell types and is required for pancreatic beta-cell growth and function. However, the consequences of overexpression of E2F1 in beta-cells are unknown.

RESEARCH DESIGN AND METHODS:

The effects of E2F1 overexpression on beta-cell proliferation and function were analyzed in isolated rat beta-cells and in transgenic mice.

RESULTS:

Adenovirus AdE2F1-mediated overexpression of E2F1 increased the proliferation of isolated primary rat beta-cells 20-fold but also enhanced beta-cell death. Coinfection with adenovirus AdAkt expressing a constitutively active form of Akt (protein kinase B) suppressed beta-cell death to control levels. At 48 h after infection, the total beta-cell number and insulin content were, respectively, 46 and 79% higher in AdE2F1+AdAkt-infected cultures compared with untreated. Conditional overexpression of E2F1 in mice resulted in a twofold increase of beta-cell proliferation and a 70% increase of pancreatic insulin content, but did not increase beta-cell mass. Glucose-challenged insulin release was increased, and the mice showed protection against toxin-induced diabetes.

CONCLUSIONS:

Overexpression of E2F1, either in vitro or in vivo, can stimulate beta-cell proliferation activity. In vivo E2F1 expression significantly increases the insulin content and function of adult beta-cells, making it a strategic target for therapeutic manipulation of beta-cell function.

PMID:
20299467
PMCID:
PMC2874704
DOI:
10.2337/db09-1295
[Indexed for MEDLINE]
Free PMC Article

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