title: The Akt/FoxO1/p27 pathway mediates the proliferative action of liraglutide             in β cells.
abstract: Numerous studies have shown that liraglutide, a modified form of human glucagon-like peptide-1 (GLP-1), increases β-cell mass. However, the underlying molecular mechanisms remain unclear. In the present study, we investigated the role of Akt/FoxO1/p27 signaling in liraglutide-induced β-cell proliferation. INS-1 rat insulinoma cells were exposed to two different concentrations of liraglutide. MTT assay was performed to evaluate β-cell proliferation. The expression of Akt/FoxO1/p27 was detected by quantitative real-time PCR and Western blotting. The results revealed that in comparison to the non-treatment group, stimulating INS-1 cells with 10 and 100 nM liraglutide caused β-cell proliferation to be significantly enhanced. The mRNA levels of p27 in INS-1 cells declined upon treatment with liraglutide compared to the non-treatment group. Western blot analysis revealed that the phosphorylation of Akt and FoxO1 was markedly elevated following exposure to liraglutide. Moreover, LY294002, a phosphatidylinositol 3-kinase (PI-3K) inhibitor, significantly abrogated liraglutide-induced effects. Therefore, we conclude that liraglutide increased the β-cell mass by upregulating β-cell proliferation and that the proliferative action of liraglutide in β cells was mediated by activation of PI-3K/Akt, which resulted in inactivation of FoxO1 and decreased p27.
authors.affiliation: Department of Endocrinology and Diabetes Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, PR China.
authors.forename: Donghong
authors.initials: D
authors.lastname: Fang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Huang
authors.forename: Hongyu
authors.initials: H
authors.lastname: Guan
authors.forename: Jianbin
authors.initials: J
authors.lastname: Liu
authors.forename: Bin
authors.initials: B
authors.lastname: Yao
authors.forename: Haipeng
authors.initials: H
authors.lastname: Xiao
authors.forename: Yanbing
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D000069450:Liraglutide; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004791:Enzyme Inhibitors; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D052216:Glucagon-Like Peptide 1; D000069450:Liraglutide; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; C085126:FOXO1 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one