Acute overexpression of lactate dehydrogenase-A perturbs β-cell mitochondrial metabolism and insulin secretion
Acute overexpression of lactate dehydrogenase-A perturbs β-cell mitochondrial metabolism and insulin secretion
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DOI：
10.2337/diabetes.49.7.1149
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发表时间：
2000-07-01
期刊：
影响因子：
7.7
通讯作者：
Rutter, GA
中科院分区：
文献类型：
--
作者：
Ainscow, EK;Zhao, C;Rutter, GA
胰岛β细胞表达低水平的乳酸脱氢酶，具有高甘油磷酸脱氢酶活性。为了确定这种构型是否有利于通过β细胞中的线粒体进行氧化葡萄糖代谢，并且对于β细胞代谢信号转导是否重要，我们已经确定了乳酸脱氢酶（LDH）-A的骨骼肌同种型的急性过表达对葡萄糖代谢和胰岛素分泌的影响。在单个MIN 6 β细胞中，LDH过表达（通过核内cDNA显微注射或腺病毒感染实现）减少了线粒体NAD（P）H增加的两个阶段对葡萄糖的反应，以及线粒体膜电位、胞浆游离ATP和胞浆游离Ca 2+的增加。在所有葡萄糖浓度下都观察到这些效应，但在次最大葡萄糖水平下最为明显。相应地，腺病毒载体介导的LDH-A过表达降低了11 mmol/l葡萄糖刺激的胰岛素分泌和随后对30 mmol/l葡萄糖刺激的反应，但当葡萄糖浓度从3 mmol/l急剧升高至30 mmol/l时，其没有显著影响。因此，LDH活性的过表达干扰胰岛β细胞类型中的正常葡萄糖代谢和胰岛素分泌，因此它可能直接导致某些形式的2型糖尿病中的胰岛素分泌缺陷。这些结果也加强了这样的观点，即葡萄糖衍生的丙酮酸代谢的葡萄糖刺激的β细胞中的胰岛素分泌的关键。
Islet beta-cells express low levels of lactate dehydrogenase and have high glycerol phosphate dehydrogenase activity. To determine whether this configuration favors oxidative glucose metabolism via mitochondria in the beta-cell and is important for beta-cell metabolic signal transduction, we have determined the effects on glucose metabolism and insulin secretion of acute overexpression of the skeletal muscle isoform of lactate dehydrogenase (LDH)-A. Monitored in single MIN6 beta-cells, LDH hyperexpression (achieved by intranuclear cDNA microinjection or adenoviral infection) diminished the response to glucose of both phases of increases in mitochondrial NAD(P)H, as well as increases in mitochondrial membrane potential, cytosolic free ATP, and cystolic free Ca2+. These effects were observed at all glucose concentrations, but were most pronounced at submaximal glucose levels. Correspondingly, adenoviral vector-mediated LDH-A overexpression reduced insulin secretion stimulated by 11 mmol/l glucose and the subsequent response to stimulation with 30 mmol/l glucose, but it was without significant effect when the concentration of glucose was raised acutely from 3 to 30 mmol/l. Thus, overexpression of LDH activity interferes with normal glucose metabolism and insulin secretion in the islet beta-cell type, and it may therefore be directly responsible for insulin secretory defects in some forms of type 2 diabetes. The results also reinforce the view that glucose-derived pyruvate metabolism in the mitochondrion is critical for glucose-stimulated insulin secretion in the beta-cell.