AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues.
AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues.
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AS160 缺陷通过多个组织的复合效应导致全身胰岛素抵抗。
DOI：
10.1042/bj20120702
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发表时间：
2013-01-15
期刊：
影响因子：
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通讯作者：
Chen S
中科院分区：
文献类型：
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作者：
Wang HY;Ducommun S;Quan C;Xie B;Li M;Wasserman DH;Sakamoto K;Mackintosh C;Chen S
AS160(Akt底物长160 kDa)是一种Rab GTP酶激活蛋白，参与胰岛素对葡萄糖转运蛋白4(GLUT4)转运的调控。在人类中，AS160一个等位基因的截断突变(R363X)降低了该蛋白的表达，并在青春期导致严重的餐后高胰岛素血症。为了补充在人类上可能进行的有限研究，我们培育了一只AS160基因敲除小鼠。在野生型小鼠中，AS160在脂肪组织和比目鱼肌中的表达相对较高，在指长伸肌中的表达较低，只有在浓缩后才能在肝脏中检测到。尽管在禁食和随机喂养条件下，AS160基因敲除小鼠的血糖水平都较低，但在一项正血糖钳夹研究中，AS160基因敲除小鼠的肌肉和肝脏都表现出胰岛素抵抗。与这种矛盾的表型相一致的是，AS160基因敲除的原代脂肪细胞的基础葡萄糖摄取量高于正常的比目鱼肌，但它们的胰岛素刺激的葡萄糖摄取量和总的GLUT4水平显著降低。相反，在EDL肌肉中，胰岛素刺激的葡萄糖摄取和GLUT4水平是正常的。肝脏还通过肝脏胰岛素抵抗、肝脏磷酸烯醇式丙酮酸羧激酶亚型表达增加和丙酮酸不耐受，导致AS160基因敲除表型，这些都表明糖异生增加。总体而言，AS160除了其催化功能外，还影响其他蛋白质的表达，其缺失不仅通过影响正常表达AS160的组织，而且还通过影响肝功能来解除基础和胰岛素调节的血糖稳态。
AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function.