Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects
Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects
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DOI：
10.2337/db07-0378
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发表时间：
2007-11-01
期刊：
影响因子：
7.7
通讯作者：
Nair, K. Sreekumaran
中科院分区：
文献类型：
--
作者：
Karakelides, Helen;Asmann, Yan W.;Nair, K. Sreekumaran
肌肉线粒体功能障碍发生在许多胰岛素抵抗状态，如2型糖尿病，促使线粒体功能障碍可能导致胰岛素抵抗的假设。我们确定的影响，胰岛素缺乏对肌肉线粒体ATP生产暂时剥夺I型糖尿病患者的胰岛素treatment.RESEARCH设计和方法，我们撤回胰岛素8.6 +/- 0.6小时在9个C-肽阴性的1型糖尿病患者和测量肌肉线粒体ATP生产和基因转录水平（基因阵列和实时定量PCR），并与胰岛素治疗的状态进行比较。我们还测量了耗氧量（间接量热法）、胰高血糖素、碳酸氢盐和其他底物的血浆水平以及尿氮。胰岛素戒断导致血糖、支链氨基酸、非酯化脂肪酸、β-羟基丁酸和尿氮增加，但碳酸氢盐无变化。胰岛素剥夺降低肌肉线粒体ATP生产率（MAPR），尽管增加全身耗氧量和改变许多肌肉线粒体基因转录的表达。参与氧化磷酸化的基因转录水平下降，而那些参与血管内皮生长因子（VEGF）的信号，炎症，细胞骨架信号，整合素信号转导途径increased. CONCLUSIONS-胰岛素缺乏和相关的代谢变化减少肌肉MAPR和氧化磷酸化基因的表达在1型糖尿病，尽管增加全身耗氧量。参与VEGF、炎症、细胞骨架和整合素信号通路的基因的转录水平增加表明可能与线粒体变化相互作用的血管因子和细胞增殖发生。
OBJECTIVE-Muscle mitochondrial dysfunction occurs in many insulin-resistant states, such as type 2 diabetes, prompting a hypothesis that mitochondrial dysfunction may cause insulin resistance. We determined the impact of insulin deficiency on muscle mitochondrial ATP production by temporarily depriving type I diabetic patients of insulin treatment.RESEARCH DESIGN AND METHODS-We withdrew insulin for 8.6 +/- 0.6 h in nine C-peptide-negative type 1 diabetic subjects and measured muscle mitochondrial ATP production and gene transcript levels (gene array and real-time quantitative PCR) and compared with insulin-treated state. We also measured oxygen consumption (indirect calorimetry); plasma levels of glucagon, bicarbonate, and other substrates; and urinary nitrogen.RESULTS-Withdrawal of insulin resulted in increased plasma glucose, branched chain amino acids, nonesterified fatty acids, P-hydroxybutyrate, and urinary nitrogen but no change in bicarbonate. Insulin deprivation decreased muscle mitochondrial ATP production rate (MAPR) despite an increase in whole-body oxygen consumption and altered expression of many muscle mitochondiial gene transcripts. Transcript levels of genes involved in oxidative phosphorylation were decreased, whereas those involved in vascular endothelial growth factor (VEGF) signaling, inflammation, cytoskeleton signaling, and integrin signaling pathways were increased.CONCLUSIONS-Insulin deficiency and associated metabolic changes reduce muscle MAPR and expression of oxidative phosphorylation genes in type 1 diabetes despite an increase in whole-body oxygen consumption. Increase in transcript levels of genes involved in VEGF, inflammation, cytoskeleton, and integrin signaling pathways suggest that vascular factors and cell proliferation that may interact with mitochondrial changes occurred.