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INCREASING GLP-1-INDUCED ß-CELL PROLIFERATION BY SILENCING THE NEGATIVE REGULATORS OF SIGNALING CREM AND DUSP14

¹Institute of Physiology
²Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
³Department of Genetic Medicine and Development, University Medical Center, University Hospital, 1211 Geneva 4, Switzerland

Objective: Glucagon-like peptide-1 (GLP-1) is a growth and differentiation factor for mature ß-cells and their precursors. However, the overall effect of GLP-1 on increasing ß-cell mass both in in vivo and in vitro conditions is relatively small and augmenting this effect would be beneficial for the treatment or prevention of both type 1 and type 2 diabetes. Here, we searched for cellular mechanisms that may limit the proliferative effect of GLP-1 and tested whether blocking them could increase ß-cell proliferation.

Research Design and Methods: We examined GLP-1-regulated genes in ßTC-Tet cells by cDNA microarrays. To assess the effect of some of these gene on cell proliferation, we reduced their expression using shRNA in ß-cell lines and primary mouse islets and measured [³H]thymidine or 5'-bromo-2'-deoxyuridine incorporation.

Results: We identified four negative regulators of intracellular signaling that were rapidly and strongly activated by GLP-1: the regulator of G protein signaling RGS2; the CREB antagonists CREM and ICERI; and the dual specificity phosphatase DUSP14, a negative regulator of the MAPK/ERK1/2 pathway. We show that knockdown of CREM or DUSP14, or expression of a dominant-negative form of DUSP14, increased ß-cell line proliferation, and enhanced the GLP-1-induced proliferation of primary ß-cells.

Conclusions: Together, our data show that: i) the cAMP/PKA/CREB and MAPK/ERK1/2 pathways can additively control ß-cell proliferation, ii) ß-cells have evolved several mechanisms limiting GLP-1-induced cellular proliferation, iii) blocking these mechanisms increases the positive effect of GLP-1 on ß-cell mass.

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