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The
th Annual Meeting of March 21-22, 2015 The Endocrine Society and The Diabetes Association of the R.O.C. (Taiwan)
DR-1
Glucagon-Like Peptide-1 Prevents ß Cells from Apoptosis through Improving Mitochondrial Function and Decreasing ER Stress via Suppressing Sustained AMPK Activation by Methylglyoxal 1
Tien-Jyun Chang, 1,2Hsing-Chi Tseng, 1,2Lee-Ming Chuang
1
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Institute of Molecular Medicine, National Taiwan University Medical College, Taipei, Taiwan
2
Objective: Accumulation of methylglyoxal (MG) contributes to glucotoxicity, and leads to β-cell apoptosis. Glucagon-like peptide-1 (GLP-1) had the protective ability against β-cell apoptosis. However, the molecular mechanism of protecting β-cell from MG-induced apoptosis by GLP-1 remains unclear. In this study, we investigated the signaling pathway involved in the anti-apoptotic effect of GLP-1. Methods: Rat insulinoma cell line, RIN-m5F cells, was used. MTT assay, annexin V/PI staining, flow cytometry for sub-G1 fraction (DNA fragmentation), western blot of active form caspase 3 and phosphorylated JNK were used as indicators of apoptosis. Extracellular flux (XF) analyses for oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were applied to estimate the mitochondrial function. Western blots of phosphorylated JNK and eIF2αwere used as indicator of ER stress. Results: MG treatment of RIN-m5F cells induced decreased cell viability with increased apoptotic markers. Besides, MG-treated cells were under increased ER stress as revealed with enhancement in phosphorylated JNK and eIF2α. Mitochondrial dysfunction was also found in the MG-treated cells. Pretreatment of GLP-1 conferred anti-apoptotic effects on MG- treated beta cells by alleviating the above abnormalities. Besides, prolonged AMPK activation was found under chronic MG incubation. Pretreatment of GLP-1 improved ATP production and decreased ER stress upon MG treatment, thus reverting cytotoxic effect from the prolonged AMPK activation. Conclusion: GLP-1 protected β-cell from MG-induced apoptosis through improving mitochondrial function and decreasing ER stress, which may be caused by prolonged AMPK activation upon MG treatment. How this feature of GLP-1 on beta cell function or beta cell mass remains to be further evaluated.
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