The role of ATM in glucose transport and insulin signaling in skeletal muscle

描述（由申请方提供）：患有缺陷型共济失调毛细血管扩张突变（ATM）的人类和动物具有胰岛素抵抗或高血糖。据报道，ATM间接影响各种细胞类型中的胰岛素信号传导，包括Akt的磷酸化。也有证据表明，ATM是一个激活激酶的AMP激活蛋白激酶（AMPK），介导胰岛素非依赖性刺激葡萄糖转运。然而，ATM在AMPK和胰岛素刺激的葡萄糖转运中的潜在作用以前没有在骨骼肌中得到解决，骨骼肌是胰岛素刺激的葡萄糖处置的主要组织。从培养的肌管的初步数据表明，一个特定的ATM抑制剂阻止胰岛素和AMPK激活剂AICAR刺激葡萄糖转运。具体目标是：1）通过AMPK活化处理来检验ATM在葡萄糖转运的胰岛素非依赖性刺激中起作用的假设（例如运动和/或AMPK激活剂AICAR），2）检验ATM在骨骼肌中胰岛素刺激的葡萄糖转运和胰岛素信号传导中起作用的假设，和3）检验ATM直接磷酸化和/或改变骨骼肌中胰岛素信号传导途径组分的活性的假设。实验工具将包括ATM缺陷转基因小鼠，ATM的特异性抑制剂，以及对ATM磷酸化的蛋白质具有特异性的抗体。阐明ATM等因子可能在AMPK或胰岛素（或两者）刺激的葡萄糖转运调节中发挥作用的可能作用，对于描述预防或治疗糖尿病的新方法具有潜在价值。 公共卫生相关声明：该项目将研究一种名为ATM的蛋白质在调节糖转运到肌肉中的潜在作用，以响应运动和胰岛素，胰岛素是一种当血糖水平升高时进入血液的激素。了解导致肌肉从血液中清除糖的因素对于制定治疗或预防糖尿病标志性高血糖浓度的策略至关重要。

DESCRIPTION (provided by applicant): Humans and animals with deficient ataxia telangiectasia mutated (ATM) are insulin-resistant or hyperglycemic. ATM reportedly indirectly influences insulin signaling, including phosphorylation of Akt, in various cell types. There is also evidence that ATM is an activating kinase for the AMP-activated protein kinase (AMPK), a mediator of insulin-independent stimulation of glucose transport. However, the potential roles of ATM in AMPK- and insulin-stimulated glucose transport have not previously been addressed in skeletal muscle, the predominant tissue in insulin-stimulated glucose disposal. Preliminary data from cultured myotubes demonstrate that a specific ATM inhibitor prevents stimulation of glucose transport by insulin and the AMPK activator AICAR. The specific aims are: 1) to test the hypothesis that ATM plays a role in insulin-independent stimulation of glucose transport by AMPK-activating treatments (e.g. exercise and/or the AMPK activator AICAR) in skeletal muscle, 2) to test the hypothesis that ATM plays a role in insulin-stimulated glucose transport and insulin signaling in skeletal muscle, and 3) to test the hypothesis that ATM directly phosphorylates and/or alters activity of components of the insulin signaling pathway in skeletal muscle. Experimental tools will include ATM deficient transgenic mice, a specific inhibitor of ATM, and an antibody specific for proteins that have been phosphorylated by ATM. Elucidating the possible role of a factor like ATM that might play a role in regulation of glucose transport stimulated by either AMPK or insulin--or both--is potentially valuable to describing new approaches to prevention or treatment of diabetes. PUBLIC HEALTH RELEVANCE STATEMENT: The project will examine the potential role of a protein called ATM in regulation of sugar transport into muscle in response to exercise and insulin, a hormone that enters the bloodstream when blood sugar levels increase. Understanding the factors that cause muscles to clear sugar from the bloodstream is vital to developing strategies to treat or prevent the high blood sugar concentrations that are the hallmark of diabetes.