Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion
Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion
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DOI：
10.1152/ajpendo.90836.2008
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发表时间：
2009-06-01
影响因子：
5.1
通讯作者：
Smith, Peter J. S.
中科院分区：
文献类型：
--
作者：
Heart, Emma;Cline, Gary W.;Smith, Peter J. S.
Heart E、Cline GW、Collis LP、Pongratz RL、Gray JP、Smith PJS。葡萄糖刺激胰岛素分泌中苹果酸酶、丙酮酸羧化和线粒体苹果酸输入的作用。美国生理学杂志内分泌代谢296：E1354-E1362，2009年。首次发表于2009年3月17日; doi：10.1152/ajpendo.90836.2008。丙酮酸循环与胰腺β细胞的葡萄糖刺激胰岛素分泌（GSIS）有关。一些丙酮酸循环途径的运作被认为需要从线粒体输出苹果酸和通过胞质苹果酸酶（ME 1）将苹果酸脱羧为丙酮酸的NADP（+）依赖性。支持和反对ME 1在GSIS中的作用的证据已经由其他人使用小干扰RNA介导的ME 1抑制提出。ME 1也被认为是琥珀酸甲酯刺激的胰岛素分泌（MSSIS）的原因，这被假设是通过琥珀酸进入线粒体以交换苹果酸和随后的苹果酸转化为丙酮酸而发生的。与大鼠相反，小鼠β细胞缺乏ME 1活性，这被认为是解释其缺乏MSSIS的原因。然而，这一假设没有得到检验。在这份报告中，我们证明，虽然腺病毒介导的ME 1过表达大大增强GSIS在大鼠胰岛素瘤INS-1 832/13细胞，它不恢复MSSIS，也没有显着影响GSIS在小鼠胰岛。INS-1 832/13细胞中ME 1过表达后GSIS的增加并没有改变ATP与ADP的比值，但伴随着苹果酸和柠檬酸水平的增加。在用苹果酸盐可渗透类似物苹果酸二甲酯处理INS-1 832/13细胞后，也观察到苹果酸盐和柠檬酸盐水平增加。这些数据表明，尽管ME 1过表达增强INS-1 832/13细胞中的回补和GSIS，但它不太可能参与胰岛中的MSSIS和GSIS。
Heart E, Cline GW, Collis LP, Pongratz RL, Gray JP, Smith PJS. Role for malic enzyme, pyruvate carboxylation, and mitochondrial malate import in glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab 296: E1354-E1362, 2009. First published March 17, 2009; doi:10.1152/ajpendo.90836.2008.-Pyruvate cycling has been implicated in glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells. The operation of some pyruvate cycling pathways is proposed to necessitate malate export from the mitochondria and NADP(+)-dependent decarboxylation of malate to pyruvate by cytosolic malic enzyme (ME1). Evidence in favor of and against a role of ME1 in GSIS has been presented by others using small interfering RNA-mediated suppression of ME1. ME1 was also proposed to account for methyl succinate-stimulated insulin secretion (MSSIS), which has been hypothesized to occur via succinate entry into the mitochondria in exchange for malate and subsequent malate conversion to pyruvate. In contrast to rat, mouse beta-cells lack ME1 activity, which was suggested to explain their lack of MSSIS. However, this hypothesis was not tested. In this report, we demonstrate that although adenoviral-mediated overexpression of ME1 greatly augments GSIS in rat insulinoma INS-1 832/13 cells, it does not restore MSSIS, nor does it significantly affect GSIS in mouse islets. The increase in GSIS following ME1 overexpression in INS-1 832/13 cells did not alter the ATP-to-ADP ratio but was accompanied by increases in malate and citrate levels. Increased malate and citrate levels were also observed after INS-1 832/13 cells were treated with the malate-permeable analog dimethyl malate. These data suggest that although ME1 overexpression augments anaplerosis and GSIS in INS-1 832/13 cells, it is not likely involved in MSSIS and GSIS in pancreatic islets.