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Increasing GLP-1-induced beta-cell proliferation by silencing the negative regulators of signaling cAMP response element modulator-alpha and DUSP14.

Abstract：

OBJECTIVE:Glucagon-like peptide-1 (GLP-1) is a growth and differentiation factor for mature beta-cells and their precursors. However, the overall effect of GLP-1 on increasing beta-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 beta-cell proliferation. RESEARCH DESIGN AND METHODS:We examined GLP-1-regulated genes in beta TC-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 beta-cell lines and primary mouse islets and measured [(3)H]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)-alpha 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 CREMalpha or DUSP14 or expression of a dominant-negative form of DUSP14 increased beta-cell line proliferation and enhanced the GLP-1-induced proliferation of primary beta-cells. CONCLUSIONS:Together, our data show that 1) the cAMP/protein kinase A/CREB and MAPK/ERK1/2 pathways can additively control beta-cell proliferation, 2) beta-cells have evolved several mechanisms limiting GLP-1-induced cellular proliferation, and 3) blocking these mechanisms increases the positive effect of GLP-1 on beta-cell mass.

journal_name

Diabetes

journal_title

Diabetes

authors

Klinger S,Poussin C,Debril MB,Dolci W,Halban PA,Thorens B

doi

10.2337/db07-1414

subject

Has Abstract

pub_date

2008-03-01 00:00:00

pages

584-93

issue

eissn

0012-1797

issn

1939-327X

pii

db07-1414

journal_volume

pub_type

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Increasing GLP-1-induced beta-cell proliferation by silencing the negative regulators of signaling cAMP response element modulator-alpha and DUSP14.