Lipid peroxidation-induced chemical modifications of insulin signaling proteins

脂质过氧化诱导的胰岛素信号蛋白化学修饰

基本信息

批准号：
8327262
负责人：
Krisztian Stadler
金额：
$ 24.65万
依托单位：
LSU PENNINGTON BIOMEDICAL RESEARCH CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-15 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8327262
关键词：
4 hydroxynonenal Acute Aftercare Aldehyde Reductase Aldehydes Animal Model Animals Atherosclerosis Attenuated Cardiovascular system Cause of Death Cells Chemicals Chronic Complications of Diabetes Mellitus Data Detection Development Diabetes Mellitus Diabetic Nephropathy Diabetic mouse Diet Disease Electron Spin Resonance Spectroscopy Enzymes Fatty acid glycerol esters Free Radical Formation Free Radicals Glucose Health Heart failure Human Hydroxyl Radical Hyperglycemia Image Impairment In Situ Incidence Inflammation Inflammatory Injection of therapeutic agent Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Insulin-Dependent Diabetes Mellitus Kidney Laboratories Lead Lipid Peroxidation Lipid Peroxides Lipids Liver Mediating Metabolic Diseases Methodology Methods Mitochondria Modeling Modification Mus NADP Neuropathy Nitrogen Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidants Oxidative Stress Oxygen Participant Pathogenesis Pathway interactions Patients Pattern Peroxonitrite Phosphorylation Prevention Process Production Proteins Rattus Receptor Signaling Retinal Diseases Rodent Role Scheme Signal Pathway Signal Transduction Signaling Protein Site Skeletal Muscle Source Spin Trapping Staging Streptozocin Stress Techniques Testing Therapeutic Agents Time Tissues Work World Health Organization Xanthines Zucker Rats base clinically relevant diabetic diabetic patient diabetic rat glycation human NOS2A protein improved in vivo inhibitor/antagonist insight insulin receptor substrate 1 protein insulin sensitivity insulin signaling insulin tolerance macrophage nitration novel oral glucose tolerance overexpression oxidation polyol research study restoration rosiglitazone type I and type II diabetes type I diabetic

项目摘要

DESCRIPTION (provided by applicant): Project summary The aim of this study is to characterize lipid peroxidation mechanisms that are interfering with the insulin signaling pathway in a type 2 diabetes model. As a result of enhanced lipid peroxidation in diabetes, toxic end- products such as 4-hydroxynonenal accumulate and may chemically modify the insulin signaling proteins, contributing to the development of insulin resistance. An emerging hypothesis relates inflammation and a proinflammatory stage as causative factors leading to the overproduction of reactive oxygen and nitrogen species (ROS/RNS) in the disease, with increasing evidence for the involvement of inducible nitric oxide synthase (iNOS) and the deleterious peroxynitrite. The expression of iNOS is upregulated by most, if not all, inducers of insulin resistance as well, and therefore considerable amount of data implies the role of the enzyme in insulin resistance-related processes. My preliminary data demonstrate that both in type 1 and type 2 diabetes, lipid radicals were formed in the liver. The extensive protein radical formation and 4- hydroxynonenal accumulation is mediated by hydroxyl radical production; the lipid radical formation and lipid peroxidation were initiated by the hydroxyl radical derived from iNOS overexpression; this finding suggests peroxynitrite involvement as a primary oxidant. Moreover, a similar pattern of lipid radical production exists in a type 2 diabetic rat model with significant iNOS involvement; and the end product 4-hydroxynonenal may interfere with the insulin signaling pathway by making chemical modification on the insulin receptor substrate protein. In this proposal, I intend to further extend these initial studies by 1 - investigating the role of iNOS- driven free radical-dependent initiation of lipid peroxidation in a model of obese type 2 diabetes; 2 - characterizing lipid peroxidation-driven mechanisms underlying the progression of insulin resistance in type 2 diabetic animals; 3 - investigating potential pharmacologic treatments to attenuate and/or delay lipid peroxidation-mediated damage and insulin resistance in type 2 diabetes. These questions compose the core of the work described in this proposal which I believe will profoundly impact our understanding of oxidative stress and free radical mechanisms in diabetes, obesity and insulin resistance.

描述（由申请人提供）：项目摘要本研究的目的是表征 2 型糖尿病模型中干扰胰岛素信号通路的脂质过氧化机制。由于糖尿病中脂质过氧化作用增强，4-羟基壬烯醛等有毒终产物会积累，并可能对胰岛素信号蛋白进行化学修饰，从而导致胰岛素抵抗的发展。一种新的假说认为，炎症和促炎阶段是导致疾病中活性氧和氮（ROS/RNS）过量产生的致病因素，越来越多的证据表明诱导型一氧化氮合酶（iNOS）和有害的过氧亚硝酸盐参与其中。大多数（如果不是全部）胰岛素抵抗诱导剂也会上调 iNOS 的表达，因此大量数据表明该酶在胰岛素抵抗相关过程中的作用。我的初步数据表明，在 1 型和 2 型糖尿病中，脂质自由基都是在肝脏中形成的。广泛的蛋白质自由基形成和 4-羟基壬烯醛的积累是由羟基自由基的产生介导的；脂质自由基的形成和脂质过氧化是由iNOS过度表达产生的羟基自由基引发的；这一发现表明过氧亚硝酸盐作为主要氧化剂参与其中。此外，在 iNOS 显着参与的 2 型糖尿病大鼠模型中也存在类似的脂质自由基产生模式。终产物4-羟基壬烯醛可能通过对胰岛素受体底物蛋白进行化学修饰而干扰胰岛素信号通路。在本提案中，我打算通过以下方式进一步扩展这些初步研究： 1 - 研究肥胖 2 型糖尿病模型中 iNOS 驱动的自由基依赖性脂质过氧化起始的作用；图2-表征2型糖尿病动物中胰岛素抵抗进展背后的脂质过氧化驱动机制； 3 - 研究潜在的药物治疗，以减轻和/或延迟 2 型糖尿病中脂质过氧化介导的损伤和胰岛素抵抗。这些问题构成了该提案中描述的工作的核心，我相信这将深刻影响我们对糖尿病、肥胖和胰岛素抵抗中氧化应激和自由基机制的理解。