AMPD1: a novel therapeutic target for reversing insulin resistance.
AMPD1: a novel therapeutic target for reversing insulin resistance.
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DOI：
10.1186/1472-6823-14-96
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发表时间：
2014-12-15
影响因子：
2.7
通讯作者：
Morisaki T
中科院分区：
文献类型：
--
作者：
Cheng J;Morisaki H;Toyama K;Sugimoto N;Shintani T;Tandelilin A;Hirase T;Holmes EW;Morisaki T
胰岛素抵抗是肥胖和II型糖尿病的标志性表现之一，逆转这种致病性异常是II型糖尿病新疗法的有吸引力的目标。二甲双胍是一种逆转胰岛素抵抗的药物，最近的一项研究表明，二甲双胍可以抑制AMP脱氨酶（AMPD）的活性。骨骼肌是导致胰岛素抵抗的主要器官之一，AMPD 1基因在骨骼肌中选择性高水平表达。认识到上述背景，我们询问AMPD 1基因的遗传破坏是否可以改善胰岛素抵抗的表现。对AMPD 1缺陷纯合小鼠和对照小鼠喂食正常食物饮食或高脂肪饮食，并进行血液分析、葡萄糖耐量试验和胰岛素耐量试验。此外，骨骼肌代谢和基因表达，包括核苷酸水平和AMP激活的蛋白激酶（AMP激酶）的激活进行了评价，在这两种条件下。AMPD 1基因的破坏导致高脂肪饮食小鼠的胰岛素抵抗状态不太严重，葡萄糖耐量改善，胰岛素清除率提高。鉴于AMP激酶在胰岛素作用中的核心作用，以及其对细胞中AMP浓度变化的反应，我们检查了AMPD 1缺陷小鼠的骨骼肌，发现它们具有更高的AMP激酶活性，这是由更高水平的磷酸化AMP激酶所证明的。这些数据表明AMPD可能是逆转胰岛素抵抗和治疗II型糖尿病的新药物靶点。本文的在线版本（doi：10.1186/1472-6823-14-96）包含补充材料，可供授权用户使用。
Insulin resistance is one of the hallmark manifestations of obesity and Type II diabetes and reversal of this pathogenic abnormality is an attractive target for new therapies for Type II diabetes. A recent report that metformin, a drug known to reverse insulin resistance, demonstrated in vitro the metformin can inhibit AMP deaminase (AMPD) activity. Skeletal muscle is one of the primary organs contributing to insulin resistance and that the AMPD1 gene is selectively expressed at high levels in skeletal muscle. Recognizing the background above, we asked if genetic disruption of the AMPD1 gene might ameliorate the manifestations of insulin resistance. AMPD1 deficient homozygous mice and control mice fed normal chow diet or a high-fat diet, and blood analysis, glucose tolerance test and insulin tolerance test were performed. Also, skeletal muscle metabolism and gene expression including nucleotide levels and activation of AMP activated protein kinase (AMP kinase) were evaluated in both conditions. Disruption of the AMPD1 gene leads to a less severe state of insulin resistance, improved glucose tolerance and enhanced insulin clearance in mice fed a high fat diet. Given the central role of AMP kinase in insulin action, and its response to changes in AMP concentrations in the cell, we examined the skeletal muscle of the AMPD1 deficient mice and found that they have greater AMP kinase activity as evidenced by higher levels of phosphorylated AMP kinase. Taken together these data suggest that AMPD may be a new drug target for the reversal of insulin resistance and the treatment of Type II diabetes. The online version of this article (doi:10.1186/1472-6823-14-96) contains supplementary material, which is available to authorized users.
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