Metformin Modulates GLP-1- and GIP-Mediated Intracellular Signaling under Normoglycemic Conditions
Metformin Modulates GLP-1- and GIP-Mediated Intracellular Signaling under Normoglycemic Conditions
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DOI：
10.4236/ojemd.2013.37036
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发表时间：
2013-11
期刊：
影响因子：
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通讯作者：
Kyoko Shinmura;T. Negoro;S. Shimizu;G. Roncador;T. Hirano;Y. Nakano
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文献类型：
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作者：
Kyoko Shinmura;T. Negoro;S. Shimizu;G. Roncador;T. Hirano;Y. Nakano
GLP-1和GIP通过诱导细胞内信号如Ca 2+和cAMP促进胰腺β细胞的胰岛素分泌。二甲双胍主要通过抑制肝脏中的葡萄糖生成和促进肌肉中的葡萄糖代谢起作用。在T2 D治疗中，它与肠促胰岛素一起用作伴随药物。我们重点研究了不同葡萄糖浓度下的细胞内信号，并评估了二甲双胍对MIN 6 β细胞中肠促胰岛素信号传导的影响。二甲双胍在5.5 mM葡萄糖存在下抑制肠促胰岛素诱导的[Ca 2 +]i，但在16.7 mM葡萄糖存在下不抑制。根据低[Ca 2 +]i，胰岛素分泌从MIN 6细胞下降，尽管增强肠促胰岛素诱导的cAMP的生产。在MIN 6细胞中检测到由Ca 2+信号负调控的Adcy 6和9的丰富表达。因此，增加cAMP产生与二甲双胍对Ca 2+动员的抑制有关。然而，我们发现二甲双胍通过抑制血糖正常条件下肠促胰岛素介导的[Ca 2 +]i来控制胰岛素分泌。
GLP-1 and GIP promote insulin secretion from pancreatic β-cells by inducing intracellular signals such as Ca2+ and cAMP. Metformin primarily acts by inhibiting glucogenesis in the liver and promoting glucose metabolism in the muscle. It is used as a concomitant drug with the incretin in the treatment of T2D. We focused on intracellular signals under various glucose concentrations and assessed the effects of metformin on incretin signaling in MIN6 β-cells. Metformin inhibited incretin-induced [Ca2+]i in the presence of 5.5 mM glucose but not 16.7 mM glucose. In accordance with low [Ca2+]i, insulin secretion from MIN6 cells declined, despite enhanced incretin-induced cAMP production. Abundant expressions of Adcy 6 and 9, which are negatively controlled by Ca2+ signals, were detected in MIN6 cells. Thus, increasing cAMP production was associated with the inhibition of Ca2+ mobilization by metformin. However, we show that metformin controls insulin secretion by inhibiting incretin-mediated [Ca2+]i under normoglycemic conditions.