title: Protective action of liraglutide in beta cells under lipotoxic stress via PI3K/Akt/FoxO1 pathway.
abstract: Liraglutide, a modified form of glucagon-like peptide-1 (GLP-1), has been found to improve beta cell function in type 2 diabetes (T2DM). However, the effect of liraglutide on beta cell function under lipotoxic stress and the underlying molecular mechanisms remain unclear. In the present study, we investigated the role of PI3K/Akt/FoxO1 signaling in liraglutide-involved beta cell protection in high free fatty acids (FFAs) condition. The apoptosis, proliferation, and insulin secretion capability of MIN6 cells and islets from C57BL/6J mice were evaluated when exposed to FFAs with/without liraglutide. The expression of effectors involved in PI3K/Akt/FoxO1signalling pathway was detected by real-time PCR and western blotting in MIN6 cells and islets from C57BL/6J mice. Liraglutide substantially inhibited the lipoapoptosis and improved the proliferation and insulin secretion of beta cells in high FFAs condition. Western blot revealed that the phosphorylation of Akt and FoxO1 was markedly decreased under lipid stress but was elevated when treated with liraglutide. Moreover, FFAs could up-regulate the expression levels of p27, Bax, Cidea but down-regulate the expression levels of Pdx-1, MafA, and NeuroD in beta cells, which was canceled by the addition of liraglutide. Moreover, LY294002, a PI3K inhibitor, could significantly abrogate all the protective actions of liraglutide against lipotoxicity. We concluded that liraglutide markedly improved beta cell function under lipid stress and that the protective action of liraglutide was mediated by activation of PI3K/Akt, which resulted in inactivation of FoxO1 along with the down-regulation of p27, Bax, Cidea and up-regulation of Pdx-1, MafA, and NeuroD expressions.
authors.affiliation: Division of Endocrinology, Tongji Hospital, Huazhong University of Science & Technology, Wuhan, 430030, P.R. China.
authors.forename: Shiying
authors.initials: S
authors.lastname: Shao
authors.forename: Mingbo
authors.initials: M
authors.lastname: Nie
authors.forename: Cai
authors.initials: C
authors.lastname: Chen
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.forename: Muxun
authors.initials: M
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Yu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D005230:Fatty Acids, Nonesterified / Q000633:toxicity; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D000069450:Liraglutide; D051473:Maf Transcription Factors, Large / Q000235:genetics; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D002867:Chromones; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005230:Fatty Acids, Nonesterified; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D052216:Glucagon-Like Peptide 1; D018398:Homeodomain Proteins; D007328:Insulin; D000069450:Liraglutide; D051473:Maf Transcription Factors, Large; D009025:Morpholines; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt; D015534:Trans-Activators; D051028:bcl-2-Associated X Protein; C112510:Cidea protein, mouse; C467200:Foxo1 protein, mouse; C485160:Mafa protein, mouse; C084010:pancreatic and duodenal homeobox 1 protein; C093564:Neurogenic differentiation factor 1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: BETA CELL FUNCTION; FORKHEAD TRANSCRIPTION FACTOR CLASS O; GLUCAGON-LIKE PEPTIDE -1; LIPOTOXICITY; TYPE 2 DIABETES MELLITUS