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The mechanism by which imeglimin inhibits gluconeogenesis in rat liver cells

机译：IMEGLIMIN抑制大鼠肝细胞中葡糖苷的机制

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Aims To understand the mechanism by which imeglimin (a new oral hypoglycemic agent whose phase 3 development program in Japan has now been completed) decreases hepatic glucose production. Materials and methods We compared the effect of imeglimin and metformin on glucose production, ATP/ADP ratio, oxygen consumption rate, mitochondrial redox potential and membrane potential in primary rat hepatocytes. Results We found that both imeglimin and metformin dose-dependently decreased glucose production and the ATP/ADP ratio. Moreover, they both increased mitochondrial redox potential (assessed by mitochondrial NAD(P)H fluorescence) and decreased membrane potential (assessed by TMRM fluorescence). However, contrary to metformin, which inhibits mitochondrial Complex I, imeglimin did not decrease the oxygen consumption rate in intact cells. By measuring the oxygen consumption of in situ respiratory chain as a function of the concentration of NADH, we observed that imeglimin decreased the affinity of NADH for the respiratory chain but did not affect its Vmax (ie competitive inhibition) whereas metformin decreased both the Vmax and the affinity (ie uncompetitive inhibition). Conclusions We conclude that imeglimin induces a kinetic constraint on the respiratory chain that does not affect its maximal activity. This kinetic constraint is offset by a decrease in the mitochondrial membrane potential, which induces a thermodynamic constraint on the ATPase responsible for a decrease in the ATP/ADP ratio.
机译：旨在了解Imeglimin（日本第3阶段开发方案已经完成的新口腔低血基缩放剂）的机制降低了肝葡萄糖生产。我们比较了IMEGLIMIN和二甲双胍对原代大鼠肝细胞的葡萄糖生产，ATP / ADP比率，氧气消耗率，线粒体氧化还原电位和膜电位的影响。结果我们发现IMEGLIMIN和二甲双胍剂量依赖性降低葡萄糖产生和ATP / ADP比率。此外，它们均增加线粒体氧化还原电位（通过线粒体NAD（P）H荧光评估）和降低的膜电位（通过TMRM荧光评估）。然而，与抑制线粒体复合物I的二甲双胍相反，IMEGLIMIN没有降低完整细胞中的氧消耗率。通过测量原位呼吸链的氧气消耗作为纳米浓度的函数，我们观察到Imeglimin降低了NADH对呼吸链的亲和力，但不影响其VMAX（即竞争抑制），而二甲双胍也降低了VMAX和亲和力（即未竞争的抑制）。结论我们得出结论，IMEGLIMIN在呼吸链上诱导不影响其最大活动的动力学约束。这种动力学约束通过线粒体膜电位的降低而被偏移，其诱导负责ATP / ADP比率降低的ATP酶的热力学约束。

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