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

描述（由申请人提供）：患有共济失调毛细血管扩张突变（ATM）缺陷的人和动物是胰岛素抵抗或高血糖。据报道，ATM间接影响各种细胞类型的胰岛素信号，包括Akt的磷酸化。也有证据表明，ATM是amp活化蛋白激酶（AMPK）的激活激酶，AMPK是胰岛素不依赖型葡萄糖转运刺激的中介。然而，ATM在AMPK和胰岛素刺激的葡萄糖运输中的潜在作用在骨骼肌中尚未得到解决，骨骼肌是胰岛素刺激的葡萄糖处理的主要组织。来自培养肌管的初步数据表明，一种特定的ATM抑制剂可以阻止胰岛素和AMPK激活剂AICAR对葡萄糖运输的刺激。具体目标是：1)验证ATM在骨骼肌中通过AMPK激活处理（如运动和/或AMPK激活剂AICAR）对葡萄糖转运的胰岛素非依赖型刺激作用的假设；2)验证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发挥作用的假设；3)验证ATM直接磷酸化和/或改变骨骼肌中胰岛素信号通路组分活性的假设。实验工具将包括有ATM缺陷的转基因小鼠，一种特异性的ATM抑制剂，以及一种针对被ATM磷酸化的蛋白质的抗体。阐明像ATM这样的因子可能在AMPK或胰岛素（或两者都有）刺激的葡萄糖运输调节中发挥作用，这对于描述预防或治疗糖尿病的新方法具有潜在的价值。

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.