AMP-activated kinase in diabetic complications

糖尿病并发症中的 AMP 激活激酶

基本信息

批准号：
7389652
负责人：
MING-HUI ZOU
金额：
$ 35.56万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
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：
2006-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7389652
关键词：
1-Phosphatidylinositol 3-Kinase 3-nitrotyrosine 5&apos -AMP-activated protein kinase Abbreviations Acetyl-CoA Carboxylase Adenosine Monophosphate Adenosine Triphosphate Adenoviruses Adverse effects Age Apolipoprotein E Arterial Fatty Streak Biological Biological Assay Blood Vessels Cardiovascular Diseases Cells Complement Complications of Diabetes Mellitus Condition Cultured Cells Cyclic GMP Data Defense Mechanisms Development Diabetes Mellitus Disease susceptibility Dominant-Negative Mutation Endothelial Cells Endothelium Enzymes Epoprostenol Event Fatty Acids Functional disorder GLUT4 gene General Population Glucose Glucose Transporter Glycerol Glycerol-3-phosphate acyltransferase Goals Health Heat-Shock Proteins 90 Human Hyperglycemia Hypoxia In Vitro Incubated Injection of therapeutic agent Insulin Insulin Resistance Ischemic Preconditioning Knock-out Knockout Mice Lead Lesion Lipid Peroxidation Lipids MAPK8 gene Measurement Metabolic stress Mitochondria Molecular Monitor Mus NG-Nitroarginine Methyl Ester National Research Service Awards Nitric Oxide Nonesterified Fatty Acids Numbers Oxidants Palmitates Pathway interactions Peroxonitrite Phosphatidylinositols Physiological reperfusion Prostacyclin synthase Prostaglandins Prostaglandins I Protein Kinase C Protein Overexpression Proteins Proto-Oncogene Proteins c-akt Reactive Nitrogen Species Reactive Oxygen Species Relaxation Reperfusion Therapy Signal Transduction Streptozocin Stress Superoxide Dismutase Superoxides Techniques Testing Thoracic aorta Time Tissues Tyrosine UCP2 protein Work arginine methyl ester biological adaptation to stress diabetes mellitus therapy diabetic human NOS3 protein imidazole-4-carboxamide improved in vivo indexing insight insulin signaling lipid metabolism nitration novel peroxisome prevent receptor riboside stress-activated protein kinase 1 type I and type II diabetes

项目摘要

Diabetes mellitus and its associated complications are a major health problem in the developed world. Diabetics are 2- to 4-times more likely to have cardiovascular diseases (CVD) than general population. One feature of diabetes that has become apparent in recent years is excess oxidant stress. In preliminary data presented here, we have found that hyperglycemia and free fatty acids (FFA), two hallmarks of type I and type II diabetes, impart an oxidant stress in endothelial cells. These results in lipid peroxiiation, tyrosine nitration of prostacyclin synthase (PGIS), reduced NO bioactivity, endothelial nitric oxide synthase (eNOS) uncoupling, and insulin resistance. We have also found that treatment with the AMP-activated kinase (AMPK) activator, 5-amino-4-imidazole carboxamide riboside (AICAR), prevents all of these events including the increase in oxidant stress and insulin resistance from occurring. A basic premise of this proposal is that AMPK activation could protect the endothelial cell against the adverse effects of hyperglycemia and FFA by increasing mitochondrial uncoupling protein (UCP)-2 that lead to a decrease in oxidant stress in parallel with an increase in NO bioactivity. Therefore, as a central hypothesis of this application, we propose that vascular diathesis of insulin resistance and diabetes is due, in part, from a hyperglycemia/FFA-induced oxidant stress and a compensatory activation of AMPK. The next part of our proposal will determine the consequences of AMPK activation on oxidant stress, endothelial function, and insulin signaling, capitalizing on preliminary data that AICAR reduces both cellular oxidant stress and insulin resistance from glucose and fatty acids in vitro and aortic lesions in Apo-E knockout (KO) enhanced by diabetes in vivo. In order to accomplish this goal, we propose to study 1). To determine if activation of AMPK by a number of means (pharmacological and molecular biological means) reduces oxidant stress and insulin resistance and to evaluate how it works, and 2). To determine if AMPK-dependent reduction in. oxidant stress and endothelial dysfunction is operating in diabetes in vivo. This powerful combination of in vitro and in vivo techniques will provide novel information as to how the metabolic stresses associated with diabetes cause damage to the endothelium. They should also yield insights into how endothelium attempts to protect itself against these stresses and whether AMPK is a potential target for therapy for diabetes.

糖尿病及其相关并发症是发达国家的一个主要健康问题。糖尿病患者患心血管疾病 (CVD) 的可能性是一般人群的 2 至 4 倍。一近年来，糖尿病的一个明显特征是过度氧化应激。初步数据显示在此介绍，我们发现高血糖和游离脂肪酸（FFA）是 I 型和 II 型糖尿病，在内皮细胞中产生氧化应激。这些结果导致脂质过氧化、酪氨酸前列环素合酶 (PGIS) 硝化、NO 生物活性降低、内皮一氧化氮合酶 (eNOS) 解偶联和胰岛素抵抗。我们还发现，使用 AMP 激活激酶进行治疗 (AMPK) 激活剂 5-氨基-4-咪唑甲酰胺核苷 (AICAR) 可预防所有这些事件包括氧化应激的增加和胰岛素抵抗的发生。这样做的一个基本前提提议认为 AMPK 激活可以保护内皮细胞免受通过增加线粒体解偶联蛋白 (UCP)-2 导致高血糖和 FFA 减少氧化应激与 NO 生物活性的增加同时发生。因此，作为本研究的中心假设在应用中，我们认为胰岛素抵抗和糖尿病的血管素质部分是由于高血糖/FFA 诱导的氧化应激和 AMPK 的代偿性激活。我们的下一部分该提案将确定 AMPK 激活对氧化应激、内皮功能和胰岛素信号传导，利用 AICAR 减少细胞氧化应激和胰岛素的初步数据体外葡萄糖和脂肪酸的抵抗力以及 Apo-E 敲除 (KO) 中的主动脉损伤体内糖尿病。为了实现这一目标，我们建议研究1)。确定是否激活 AMPK 通过多种方式（药理学和分子生物学方式）减少氧化应激和胰岛素抵抗并评估其工作原理，以及 2)。确定 AMPK 依赖性减少是否存在。氧化应激和内皮功能障碍正在糖尿病体内发挥作用。这种强大的组合在体外和体内技术将提供关于代谢应激如何与糖尿病会导致内皮细胞损伤。他们还应该深入了解内皮细胞如何尝试保护自身免受这些压力以及 AMPK 是否是糖尿病治疗的潜在靶点。