Ectopic expression of E2F1 stimulates beta cell proliferation and function

Gael Grouwels, Ying Cai, Inge Hoebeke, Gunter Leuckx, Yves Heremans, U Siebold, Geert Stange, Marie Chintinne, Zhidong Ling, Daniel Pipeleers, Henry Heimberg, Mark Van De Casteele

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23 Citations (Scopus)
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Abstract

Objective - Generating functional beta cells by inducing their proliferation might open perspectives for cell therapy in diabetes. Transcription factor E2F1 controls G1- 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. Co-infection with adenovirus AdAkt expressing a constitutively active form of Akt (protein kinase B) suppressed beta cell death to control levels. At 48h post-infection, the total beta cell number and insulin content were respectively 46% and 79% higher in AdE2F1+AdAkt-infected cultures as compared to untreated. Conditional overexpression of E2F1 in mice resulted in a 2-fold increase of beta cell proliferation and 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.
Original languageEnglish
Pages (from-to)1435-1444
Number of pages10
JournalDiabetes
Volume59
Issue number6
Publication statusPublished - 2010

Keywords

  • proliferation
  • mice
  • cell death
  • E2f1

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