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

ATM 在骨骼肌葡萄糖转运和胰岛素信号传导中的作用

• 批准号: 7840929
• 负责人: JONATHAN S. FISHER
• 金额: $ 8.46万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840929
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Address; Adipocytes; Animals; Antibodies; Blood Circulation; Blood Glucose; Cells; Data; Diabetes Mellitus; Exercise; GLUT4 gene; Goals; Hormones; Human; Hyperglycemia; Insulin; Insulin Resistance; Insulin Signaling Pathway; Mus; Muscle; Muscle Fibers; Phosphorylation; Play; Prevention approach; Proteins; Regulation; Role; Site; Skeletal Muscle; Testing; Tissues; Transgenic Mice; ataxia telangiectasia mutated protein; cell type; glucose disposal; glucose transport; glucose uptake; impaired glucose tolerance; inhibitor/antagonist; insulin mediators; insulin signaling; member; novel strategies; phosphoinositide-dependent kinase 1; prevent; public health relevance; response; sugar; tool

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.

描述（由申请人提供）：毛细血管理突变（ATM）的人类和动物是胰岛素耐药或高血糖。据报道，ATM在各种细胞类型中间接影响胰岛素信号传导，包括AKT的磷酸化。也有证据表明，ATM是AMP激活蛋白激酶（AMPK）的激活激酶，这是胰岛素非依赖性葡萄糖转运的介质。然而，以前在骨骼肌中未解决ATM在AMPK和胰岛素刺激的葡萄糖转运中的潜在作用，骨骼肌是胰岛素刺激的葡萄糖处置中的主要组织。来自培养的肌管的初步数据表明，特定的ATM抑制剂可防止胰岛素和AMPK激活剂AICAR刺激葡萄糖转运。具体目的是：1）检验以下假说，即ATM通过AMPK激活治疗（例如运动和/或AMPK激活剂AICAR）在胰岛素独立刺激葡萄糖转运中起作用，2）在测试ATM在胰岛素刺激的传输中扮演胰岛素的传输和胰岛素序列，以测试ATM在胰岛素中扮演的作用。 ATM直接磷酸化和/或改变骨骼肌中胰岛素信号通路的成分活性。实验工具将包括ATM缺乏的转基因小鼠，ATM的特异性抑制剂，以及针对已被ATM磷酸化的蛋白质特异的抗体。阐明像ATM这样的因素可能在调节AMPK或胰岛素或两者兼而有之的葡萄糖转运中起作用的可能作用，对于描述预防或治疗糖尿病的新方法可能是有价值的。 公共卫生相关性声明：该项目将检查一种称为ATM的蛋白质在响应运动和胰岛素的糖转运糖转运中的蛋白质的潜在作用，这是一种激素，当血糖水平升高时进入血液。了解导致肌肉从血液中清除糖的因素对于制定治疗或防止糖尿病标志的高血糖浓度的策略至关重要。