Mitochondrial Metabolism of Pyruvate Is Essential for Regulating Glucose-stimulated Insulin Secretion
Mitochondrial Metabolism of Pyruvate Is Essential for Regulating Glucose-stimulated Insulin Secretion
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DOI：
10.1074/jbc.m113.521666
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发表时间：
2014-05-09
影响因子：
4.8
通讯作者：
Joseph, Jamie W.
中科院分区：
文献类型：
--
作者：
Patterson, Jessica N.;Cousteils, Katelyn;Joseph, Jamie W.
背景：丙酮酸代谢在胰腺细胞中起着重要作用。结果：药理作用和siRNA介导的抑制线粒体丙酮酸载体-1和-2抑制细胞代谢和胰岛素分泌。结论：丙酮酸进入细胞线粒体是调节胰岛素释放的关键。意义：丙酮酸的线粒体代谢在响应控制胰岛素释放的营养物质的信号中起着关键作用。众所周知，丙酮酸的线粒体代谢对胰岛素的分泌至关重要；然而，我们对丙酮酸如何运输到细胞内的线粒体知之甚少。缺乏了解的部分原因是携带者基因在2012年才被发现。在目前的研究中，我们评估了最近发现的载体在调节胰岛素分泌中的作用。我们的研究表明，细胞同时表达线粒体丙酮酸载体(MPC1和MPC2)。利用药物抑制剂和siRNA介导的MPC基因敲除，我们证明了该载体在调节克隆832/13细胞以及大鼠和人胰岛的胰岛素分泌方面发挥了关键作用。我们还表明，MPC是ATP调节的钾(K-ATP)通道依赖性和非依赖性胰岛素分泌途径的重要调节器。抑制MPC可阻断葡萄糖刺激胰岛素分泌的两个关键信号分子的增加，即ATP/ADP比率和NADPH/NADP(+)比率。MPC还在体内葡萄糖稳态中发挥作用，因为药物抑制剂氰基-(1-苯基吲哚-3-基)-丙烯酸酯(UK5099)对MPC的抑制导致糖耐量受损。这些研究清楚地表明，新发现的线粒体丙酮酸载体位于营养代谢的重要分支点，是胰岛素分泌的重要调节因子。
Background: Pyruvate metabolism plays an essential role in pancreatic -cells. Results: Pharmacological and siRNA-mediated inhibition of mitochondrial pyruvate carrier-1 and -2 inhibit -cell metabolism and insulin secretion. Conclusion: Pyruvate entry into -cell mitochondria is critical for regulating insulin release. Significance: Mitochondrial metabolism of pyruvate plays a key role in generating signals in response to nutrients that control insulin release.It is well known that mitochondrial metabolism of pyruvate is critical for insulin secretion; however, we know little about how pyruvate is transported into mitochondria in -cells. Part of the reason for this lack of knowledge is that the carrier gene was only discovered in 2012. In the current study, we assess the role of the recently identified carrier in the regulation of insulin secretion. Our studies show that -cells express both mitochondrial pyruvate carriers (Mpc1 and Mpc2). Using both pharmacological inhibitors and siRNA-mediated knockdown of the MPCs we show that this carrier plays a key role in regulating insulin secretion in clonal 832/13 -cells as well as rat and human islets. We also show that the MPC is an essential regulator of both the ATP-regulated potassium (K-ATP) channel-dependent and -independent pathways of insulin secretion. Inhibition of the MPC blocks the glucose-stimulated increase in two key signaling molecules involved in regulating insulin secretion, the ATP/ADP ratio and NADPH/NADP(+) ratio. The MPC also plays a role in in vivo glucose homeostasis as inhibition of MPC by the pharmacological inhibitor -cyano--(1-phenylindol-3-yl)-acrylate (UK5099) resulted in impaired glucose tolerance. These studies clearly show that the newly identified mitochondrial pyruvate carrier sits at an important branching point in nutrient metabolism and that it is an essential regulator of insulin secretion.