p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD
p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD
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DOI：
10.1681/asn.2012050503
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发表时间：
2013-01-01
影响因子：
13.6
通讯作者：
Soulage, Christophe O.
中科院分区：
文献类型：
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作者：
Koppe, Laetitia;Pillon, Nicolas J.;Soulage, Christophe O.
经常伴随CKD的胰岛素抵抗的机制尚不清楚，但肾脏排泄化合物的保留可能起作用。其中一种化合物是对甲酰硫酸盐（PCS），这是一种蛋白质结合的尿毒症毒素，起源于肠道微生物的酪氨酸代谢。在这里，我们试图确定PCS是否与ckd相关的胰岛素抵抗有关。给肾脏功能正常的小鼠服用PCS 4周，会引发胰岛素抵抗、脂肪量减少、肌肉和肝脏脂质异位再分布，模拟CKD的相关特征。经PCS处理的小鼠通过ERK1/2激活显示骨骼肌胰岛素信号的改变。此外，将C2C12肌管暴露于CKD中观察到的PCS浓度下，通过直接激活ERK1/2引起胰岛素抵抗。肾次全切除术导致小鼠胰岛素抵抗和血脂异常，用阿拉伯低聚木糖治疗，通过减少肠道对甲酚的产生来降低血清PCS，防止这些代谢紊乱。综上所述，这些数据表明PCS有助于胰岛素抵抗，针对PCS可能是CKD的一种治疗策略。[J]中国生物医学工程学报，2013,31(2):444 - 444。doi: 10.1681 / ASN.2012050503
The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD. J Am Soc Nephrol 24: 88-99, 2013. doi: 10.1681/ASN.2012050503