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

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Abstract
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)-α 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 CREMα 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.