title: Glucagon-like peptide-1 prevents methylglyoxal-induced apoptosis of beta cells through improving mitochondrial function and suppressing prolonged AMPK activation.
abstract: Accumulation of methylglyoxal (MG) contributes to glucotoxicity and mediates beta cell apoptosis. The molecular mechanism by which GLP-1 protects MG-induced beta cell apoptosis remains unclear. Metformin is a first-line drug for treating type 2 diabetes associated with AMPK activation. However, whether metformin prevents MG-induced beta cell apoptosis is controversial. Here, we explored the signaling pathway involved in the anti-apoptotic effect of GLP-1, and investigated whether metformin had an anti-apoptotic effect on beta cells. MG treatment induced apoptosis of beta cells, impaired mitochondrial function, and prolonged activation of AMP-dependent protein kinase (AMPK). The MG-induced pro-apoptotic effects were abolished by an AMPK inhibitor. Pretreatment of GLP-1 reversed MG-induced apoptosis, and mitochondrial dysfunction, and suppressed prolonged AMPK activation. Pretreatment of GLP-1 reversed AMPK activator 5-aminoimidazole-4-carboxamide riboside (AICAR)-induced apoptosis, and suppressed prolonged AMPK activation. However, metformin neither leads to beta cell apoptosis nor ameliorates MG-induced beta cell apoptosis. In parallel, GLP-1 also prevents MG-induced beta cell apoptosis through PKA and PI3K-dependent pathway. In conclusion, these data indicates GLP-1 but not metformin protects MG-induced beta cell apoptosis through improving mitochondrial function, and alleviating the prolonged AMPK activation. Whether adding GLP-1 to metformin provides better beta cell survival and delays disease progression remains to be validated.
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.
authors.forename: Tien-Jyun
authors.initials: TJ
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.|Institute of Molecular Medicine, National Taiwan University Medical College, Taipei 10002, Taiwan.
authors.forename: Hsing-Chi
authors.initials: HC
authors.lastname: Tseng
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.
authors.forename: Meng-Wei
authors.initials: MW
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.|Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Medical College, Taipei 10002, Taiwan.|Institute of Biomedical Science, Academia Sinica, Taipei, 11500, Taiwan.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, National Taiwan University Medical College, Taipei 10002, Taiwan.
authors.forename: Meng-Lun
authors.initials: ML
authors.lastname: Hsieh
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 10002, Taiwan.|Institute of Molecular Medicine, National Taiwan University Medical College, Taipei 10002, Taiwan.
authors.forename: Lee-Ming
authors.initials: LM
authors.lastname: Chuang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011765:Pyruvaldehyde / Q000633:toxicity*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007004:Hypoglycemic Agents; D011765:Pyruvaldehyde; D052216:Glucagon-Like Peptide 1; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases