AMPK and Mechanisms of Glucose Toxicity

AMPK 和葡萄糖毒性机制

基本信息

批准号：
7575756
负责人：
NEIL B RUDERMAN
金额：
$ 25.19万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575756
关键词：
2,4-thiazolidinedione 5&apos -AMP-activated protein kinase Acetyl-CoA Carboxylase Alanine Animals Cells Complement Coronary heart disease Data Development Diabetes Mellitus Disease Distal Dominant-Negative Mutation Enzymes Event Experimental Diabetes Mellitus Functional disorder Genetic Glucose Glycogen Hepatocyte Human Hyperglycemia In Vitro Incubated Insulin Insulin Resistance Lead Lipids Liver Malonyl Coenzyme A Mediating Metabolic syndrome Metformin Modeling Molecular Muscle Muscle Cells Mutate Non-Insulin-Dependent Diabetes Mellitus Oxidative Stress Pathogenesis Patients Phosphorylation Site Phosphotransferases Play Preparation Prevention Public Health RNA Interference Rattus Refractory Regulation Research Research Personnel Role Secondary to Signal Transduction Skeletal Muscle Small Interfering RNA Study models System Technology Testing Thiazolidinediones Time Tissues Toxic effect Viral base cellular transduction hepatoma cell human FRAP1 protein in vivo in vivo Model inhibitor/antagonist insulin sensitivity insulin signaling knock-down lipid metabolism malonyl-CoA decarboxylase mutant novel overexpression oxidant stress premature prevent protective effect research study sensor therapeutic target tool

项目摘要

In patients with diabetes and experimental animals sustained hyperglycemia leads to insulin resistance in both liver and muscle. Data obtained by us in a number of models suggest that such glucose-induced insulin resistance is related to dysregulation of the AMP-activated protein kinase (AMPK)/malonyl CoAfuel sensing and signaling network (diminished AMPK activity and/or an increase in malonyl CoA concentration). The proposed studies will test this hypothesis in two of these models, cultured hepatocytes exposed to a high ambient glucose concentration (Aim 1) and glucose-infused rats (Aim 3), in both of which we have observed the aforementioned changes in AMPK and malonyl CoA, and, where studied, an impaired ability of insulin to activate Akt. In addition, we will attempt to develop a cell-based system for testing this hypothesis in muscle using C2C12 cells (Aim 2). We will determine in each of these models how changes in AMPK relate temporally to impaired insulin signaling (Akt, IRS-PY), alterations in lipid metabolites (malonyl CoA, DAG, LCCoA) and putative downstream pathogenetic events (e.g., PKC, IKKB-NF*B activation). In addition, using RNAi silencing, viral constructs and/or pharmacological agents as tools, we will determine whether the changes in AMPK and malonyl CoA play a causal role. Finally, we will explore possible mechanisms for the decrease in AMPK activity in the glucose-infused rats. These studies will provide a rigorous test of the hypothesis that dysregulation of the AMPK/malonyl CoA network can be both a cause of glucose-induced insulin resistance and a target for its therapy. They will also provide a potentially novel framework for understanding the pathogenesis and treatment of insulin resistance, a problem that antedates type 2 diabetes, premature coronary heart disease, NAFLD/NASH and other disorders associated with the metabolic syndrome. Thus, they could have an important impact on public health.

糖尿病患者和实验动物持续高血糖会导致胰岛素抵抗肝脏和肌肉。我们在许多模型中获得的数据表明，这种葡萄糖诱导的胰岛素抵抗与 AMP 激活蛋白激酶 (AMPK)/丙二酰辅酶 Afuel 的失调有关传感和信号网络（AMPK 活性降低和/或丙二酰辅酶 A 浓度增加）。拟议的研究将在其中两个模型中测试这一假设，即培养的肝细胞暴露于高环境葡萄糖浓度（目标 1）和注射葡萄糖的大鼠（目标 3），在这两种情况下，我们都有观察到上述 AMPK 和丙二酰辅酶 A 的变化，并且在研究中发现能力受损胰岛素激活 Akt。此外，我们将尝试开发一个基于细胞的系统来测试这一点使用 C2C12 细胞在肌肉中的假设（目标 2）。我们将确定每个模型如何变化 AMPK 与胰岛素信号传导受损（Akt、IRS-PY）、脂质代谢物的改变暂时相关（丙二酰辅酶 A、DAG、LCCoA）和假定的下游致病事件（例如 PKC、IKKB-NF*B）激活）。此外，使用 RNAi 沉默、病毒构建体和/或药物制剂作为工具，我们将确定 AMPK 和丙二酰辅酶 A 的变化是否起到因果作用。最后我们将探讨输注葡萄糖的大鼠中 AMPK 活性降低的可能机制。这些研究将为 AMPK/丙二酰辅酶 A 失调的假设提供严格的检验。网络既可能是葡萄糖诱导的胰岛素抵抗的原因，也是其治疗的目标。他们会还为理解胰岛素的发病机制和治疗提供了一个潜在的新框架抵抗力是 2 型糖尿病、早发冠心病、NAFLD/NASH 之前出现的问题与代谢综合征相关的其他疾病。因此，它们可能会产生重要影响公共卫生。