Retention of acetylcarnitine in chronic kidney disease causes insulin resistance in skeletal muscle.
Retention of acetylcarnitine in chronic kidney disease causes insulin resistance in skeletal muscle.
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DOI：
10.3164/jcbn.15-146
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发表时间：
2016-11
影响因子：
2.4
通讯作者：
Kobayashi M
中科院分区：
文献类型：
--
作者：
Miyamoto Y;Miyazaki T;Honda A;Shimohata H;Hirayama K;Kobayashi M
胰岛素抵抗常见于慢性肾病患者。然而，胰岛素抵抗与慢性肾脏疾病相关的机制尚不清楚。众所周知，线粒体乙酰辅酶a (AcCoA)/CoA比值的增加导致骨骼肌胰岛素抵抗，而该比值受肉碱乙酰转移酶的调节，该酶在CoA和肉碱之间交换乙酰基部分。由于AcCoA的过量乙酰基部分以乙酰肉碱的形式在尿中排泄，我们假设乙酰肉碱的滞留可能是慢性肾病患者胰岛素抵抗的一个原因。慢性肾病患者血清乙酰肉碱浓度测定，随着肾功能的降低，乙酰肉碱浓度显著升高。在体外培养的骨骼肌细胞（C2C12和人肌管）中，研究了过量的细胞外乙酰肉碱对胰岛素抵抗的影响，发现添加乙酰肉碱能显著且剂量依赖性地抑制胰岛素依赖型葡萄糖摄取。添加的乙酰肉碱通过肉碱乙酰转移酶逆反应转化为肉碱，使线粒体中AcCoA浓度和AcCoA/CoA比值显著升高。结果提示CKD患者血清乙酰肉碱升高通过刺激肉碱乙酰转移酶逆反应引起线粒体AcCoA积累，导致骨骼肌胰岛素抵抗。
Insulin resistance occurs frequently in patients with chronic kidney disease. However, the mechanisms of insulin resistance associated with chronic kidney disease are unclear. It is known that an increase in the mitochondrial acetyl-CoA (AcCoA)/CoA ratio causes insulin resistance in skeletal muscle, and this ratio is regulated by carnitine acetyltransferase that exchanges acetyl moiety between CoA and carnitine. Because excess acetyl moiety of AcCoA is excreted in urine as acetylcarnitine, we hypothesized that retention of acetylcarnitine might be a cause of insulin resistance in chronic kidney disease patients. Serum acetylcarnitine concentrations were measured in chronic kidney disease patients, and were significantly increased with reduction of renal function. The effects of excess extracellular acetylcarnitine on insulin resistance were studied in cultured skeletal muscle cells (C2C12 and human myotubes), and insulin-dependent glucose uptake was significantly and dose-dependently inhibited by addition of acetylcarnitine. The added acetylcarnitine was converted to carnitine via reverse carnitine acetyltransferase reaction, and thus the AcCoA concentration and AcCoA/CoA ratio in mitochondria were significantly elevated. The results suggest that increased serum acetylcarnitine in CKD patients causes AcCoA accumulation in mitochondria by stimulating reverse carnitine acetyltransferase reaction, which leads to insulin resistance in skeletal muscle.
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DOI：
10.1152/ajpendo.00312.2005
发表时间：
2006-03-01
影响因子：
5.1
作者：
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通讯作者：
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影响因子：
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影响因子：
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作者：
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Fliser, D
影响因子：
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作者：
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