Article: article from journal or magazin.
Increasing GLP-1-induced beta-cell proliferation by silencing the negative regulators of signaling cAMP response element modulator-alpha and DUSP14.
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.
Animals, Cell Line, Cell Proliferation/drug effects, Cells, Cultured, Cyclic AMP Response Element Modulator/genetics, Cyclic AMP Response Element Modulator/metabolism, Dose-Response Relationship, Drug, Dual-Specificity Phosphatases/genetics, Dual-Specificity Phosphatases/metabolism, Gene Expression Profiling, Gene Silencing, Glucagon-Like Peptide 1/pharmacology, Glucose/metabolism, Glucose/pharmacology, Humans, Insulin-Secreting Cells/cytology, Insulin-Secreting Cells/drug effects, Male, Mice, Oligonucleotide Array Sequence Analysis, Peptides/pharmacology, RGS Proteins/genetics, RGS Proteins/metabolism, Venoms/pharmacology
Web of science
Last modification date