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Increasing GLP-1–Induced β-Cell Proliferation by Silencing the Negative Regulators of Signaling cAMP Response Element Modulator- and DUSP14

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

Address correspondence and reprint requests to Bernard Thorens, University of Lausanne, Center for Integrative Genomics, Génopode Building, 1015 Lausanne, Switzerland. E-mail: bernard.thorens{at}unil.ch

Key Words: CREB, cAMP response element-binding protein • CREM, cAMP response element modulator • DMEM, Dulbecco's modified Eagle's medium • ERK1/2, extracellular signal-regulated kinase 1/2 • FACS, fluorescence-activated cell sorter • FBS, fetal bovine serum • GAPDH, glyceraldehyde-3-phosphate dehydrogenase • GFP, green fluorescent protein • GLP-1, glucagon-like peptide-1 • MAPK, mitogen-activated protein kinase • PI 3-kinase, phosphatidylinositol 3-kinase • PKA, protein kinase A

OBJECTIVE—Glucagon-like peptide-1 (GLP-1) is a growth and differentiation factor for mature β-cells and their precursors. However, the overall effect of GLP-1 on increasing β-cell mass in both in vivo and in vitro conditions is relatively small, and augmenting this effect would be beneficial for the treatment or prevention of 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 β-cell proliferation.

RESEARCH DESIGN AND METHODS—We examined GLP-1–regulated genes in βTC-Tet cells by cDNA microarrays. To assess the effect of some of these gene on cell proliferation, we reduced their expression using small heterogenous RNA in β-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 cAMP response element-binding protein (CREB) antagonists cAMP response element modulator (CREM)- and ICERI; and the dual specificity phosphatase DUSP14, a negative regulator of the mitogen-activated protein kinase (MAPK)/extracellular signal–regulated kinase 1/2 (ERK1/2) pathway. We show that knockdown of CREM or DUSP14 or expression of a dominant-negative form of DUSP14 increased β-cell line proliferation and enhanced the GLP-1–induced proliferation of primary β-cells.

CONCLUSIONS—Together, our data show that 1) the cAMP/protein kinase A/CREB and MAPK/ERK1/2 pathways can additively control β-cell proliferation, 2) β-cells have evolved several mechanisms limiting GLP-1–induced cellular proliferation, and 3) blocking these mechanisms increases the positive effect of GLP-1 on β-cell mass.

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