title: The human glucagon-like peptide-1 analogue liraglutide regulates pancreatic beta-cell proliferation and apoptosis via an AMPK/mTOR/P70S6K signaling pathway.
abstract: Glucagon-like peptide-1 (GLP-1), an effective therapeutic agent for the treatment of diabetes, has been proven to protect pancreatic beta cells through many pathways. Recent evidence demonstrates that AMP-activated protein kinase (AMPK), as a metabolic regulator, coordinates beta-cell protein synthesis through regulation of the mammalian target of rapamycin (mTOR) signaling pathway. The purpose of the present study was to explore whether liraglutide, a human GLP-1 analogue, protects beta cells via AMPK/mTOR signaling. We evaluated INS-1 beta-cell line proliferation using the Cell Counting Kit-8, and examined the effect of GLP-1 on cellular ATP levels using an ATP assay kit. mTOR pathway protein expression levels were tested by Western blotting and glucolipotoxicity-induced cell apoptosis was evaluated by flow cytometry. Liraglutide increased beta-cell viability at an optimum concentration of 100 nmol/L in the presence of 11.1 or 30 mmol/L glucose. Liraglutide (100 nmol/L) activated mTOR and its downstream effectors, 70-kDa ribosomal protein S6 kinase and eIF4E-binding protein-1, in INS-1 cells. This effect was abated by pathway blockers: the AMPK activator AICAR and the mTOR inhibitor rapamycin. Furthermore, the effect of liraglutide on beta-cell proliferation was inhibited by AICAR and rapamycin. Liraglutide increased cellular ATP levels. In addition, liraglutide protected beta cells from glucolipotoxicity-induced apoptosis. This response was also prevented by rapamycin treatment. These results suggest that the enhancement of beta-cell proliferation by that GLP-1 receptor agonist liraglutide is mediated, at least in part, by AMPK/mTOR signaling. Liraglutide also prevents beta-cell glucolipotoxicity by activating mTOR.
authors.affiliation: Department of Geriatric Endocrinology, General Hospital of PLA, 100853 Beijing, China.
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Miao
authors.forename: Zhao-Yan
authors.initials: ZY
authors.lastname: Gu
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hu
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Gong
authors.forename: Hua
authors.initials: H
authors.lastname: Shu
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D018797:Cell Cycle Proteins; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology*; D000069450:Liraglutide; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012265:Ribonucleotides / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D007004:Hypoglycemic Agents; D010750:Phosphoproteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase; C031143:AICA ribonucleotide; D020123:Sirolimus