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：
7585276
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/7585276
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 Cellular Stress Complement Complications of Diabetes Mellitus 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 Palmitates Pathway interactions Peroxonitrite Phosphatidylinositols Prostacyclin synthase Prostaglandins Prostaglandins I Protein Kinase C 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 overexpression oxidant stress 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主要健康问题。糖尿病患者患心血管疾病（CVD）的可能性高2到4倍。一近年来糖尿病的特征是过量的氧化应激。在初步数据中在这里提出的是，我们发现高血糖和游离脂肪酸（FFA），I型的两个标志和 II型糖尿病，在内皮细胞中赋予氧化应激。这些结果导致脂质过氧，酪氨酸前列环蛋白合酶（PGI）的硝化，无生物活性，内皮一氧化氮合酶（ENOS）解偶联和胰岛素抵抗。我们还发现用AMP激活激酶治疗（AMPK）激活剂，5-氨基-4-咪唑羧酰胺核苷（AICAR），可防止所有这些事件包括氧化应激的增加和发生的胰岛素抵抗。一个基本前提建议是AMPK激活可以保护内皮细胞免受不利影响通过增加线粒体解偶联蛋白（UCP）-2的高血糖和FFA，导致减少氧化应激并联，无生物活性。因此，作为对此的核心假设应用，我们建议胰岛素抵抗和糖尿病的血管核心部分是由于高血糖/FFA诱导的氧化应激和AMPK的补偿性激活。我们的下一部分建议将确定AMPK激活对氧化应激，内皮功能和胰岛素信号传导，利用AICAR降低细胞氧化剂和胰岛素的初步数据体外葡萄糖和脂肪酸的耐药性在Apo-E敲除（KO）中的主动脉损伤（KO）的抗性。体内糖尿病。为了实现这一目标，我们建议研究1）。确定激活是否激活通过多种均值（药理和分子生物学手段）的AMPK减少了氧化应激和胰岛素抵抗并评估其工作原理，2）。确定AMPK依赖性降低。氧化应激和内皮功能障碍在体内糖尿病中工作。这种强大的组合体外和体内技术将提供有关与代谢应力如何相关的新信息糖尿病会损害内皮。他们还应该对内皮如何尝试产生见解保护自己免受这些压力以及AMPK是否是治疗糖尿病的潜在靶标。