Targeting Inflammation to Improve Endothelial Function in Type 2 Diabetes: A Subs

针对炎症改善 2 型糖尿病的内皮功能：A Subs

基本信息

批准号：
7546667
负责人：
MARK A CREAGER
金额：
$ 37.34万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7546667
关键词：
1-Phosphatidylinositol 3-Kinase 3-nitrotyrosine Accounting Amputation Animals Anti-Inflammatory Agents Anti-inflammatory Arteries Aspirin Atherosclerosis Biological Availability Blood Vessels C-reactive protein CD40 Ligand Calories Cardiovascular Diseases Cardiovascular system Cause of Death Cerebrovascular Disorders Chronic Clinical Trials Design Coronary Arteriosclerosis Cyclooxygenase Inhibitors Development Diabetes Mellitus Diet Diffuse Dose Dyslipidemias Endothelium Enzymes Epidemic Event Fatty acid glycerol esters Funding Generic Drugs Hemorrhage Homeostasis Human IkappaB kinase Inflammation Inflammation Mediators Inflammatory Injury Insulin Insulin Receptor Insulin Resistance Interleukin-6 Investigation Laboratories Lead Masks Measures Mediating Metabolic Morbidity - disease rate Myocardial Infarction NF-kappa B NFKB Signaling Pathway Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Oxidative Stress Pathogenesis Pathway interactions Patients Peripheral Peripheral arterial disease Pharmaceutical Preparations Pharmacologic Substance Placebo Control Placebos Prevalence Process Production Proto-Oncogene Proteins c-akt Randomized Regulation Resolution Risk Rodent Role Safety Serum Severities Signal Pathway Stroke Syndrome TNF gene Testing Time Tumor Necrosis Factor Receptor Tumor Necrosis Factor-alpha Tumor Necrosis Factors Ultrasonography United States United States National Institutes of Health Vascular Diseases Vasodilation abstracting adipokines adiponectin brachial artery cytokine diabetes management dimer disability genetic regulatory protein human NOS3 protein improved inflammatory marker inhibitor/antagonist insulin sensitivity mortality placebo controlled study prevent salicylate salicylsalicylic acid sugar

项目摘要

DESCRIPTION (provided by applicant): Atherosclerosis is the principal cause of death and disability in patients with diabetes mellitus. Diabetes exerts its pro-atherogenic actions, at least in part, by disturbing endothelial homeostasis. Insulin resistance states, including type 2 diabetes mellitus, are associated with decreased bioavailability of endothelium-derived nitric oxide (NO) and impaired endothelium-dependent vasodilation, and impaired endothelial function predicts cardiovascular events. Basic studies suggest that insulin receptor mediated activation of the PI-3 kinase pathway is important for normal endothelial nitric oxide synthase (eNOS) function. Recent studies demonstrate an important role for subacute, chronic inflammation, specifically mediated by the IKK¿/NF-kB pathway, in the development of insulin resistance and type 2 diabetes mellitus. We hypothesize that activation of IKK¿/NF-kB signaling pathways contributes to the development of atherosclerosis in patients with diabetes, in part by decreasing the bioavailability of nitric oxide and impairing endothelial function. Salicylates inhibit the NF-kB regulatory protein IKK¿, downregulate NF-kB activation, and appear to ameliorate insulin resistance and its associated metabolic abnormalities. Accordingly, we plan to determine whether inhibition of I[kappa] B kinase [beta] (IKK¿)/NF-[kappa]B, a master regulator of inflammation, with salsalate, will restore endothelium-dependent vasodilation in patients with type 2 diabetes. This is proposed as a substudy of TINSAL-T2D (Targeting INflammation using SALsalate for Type 2 Diabetes), a study funded by the NIH (No. UO1-DK074556). The overall objective of TINSAL-T2D is to determine whether salicylates represent a new pharmacological option for diabetes management. In this multicenter, double-masked, placebo-controlled trial, we will target inflammation using salsalate to study its effects on endothelial function and atherosclerotic risk. Flow mediated, endothelium-dependent vasodilation of the brachial (conduit) artery will be measured by high resolution vascular ultrasonography in patients with type 2 diabetes. In addition, change in endothelial function will be assessed as a function of change in glycemia and in circulating inflammatory mediators, as well as free fatty acids, adiponectin, and nitrotyrosine. It is anticipated that findings from this investigation will uncover an important pathophysiologic mechanism that accounts for abnormal vascular function and identify a potential therapy to reduce the risk of adverse cardiovascular events in patients with type 2 diabetes. This investigation is timely and important as it may provide the first information to suggest that targeting inflammation directly may improve endothelial function and atherosclerotic risk in patients with type 2 diabetes. These studies may provide initial evidence of a new pharmacologic strategy to treat or prevent cardiovascular disease in patients with diabetes or related insulin resistant syndromes associated with subacute chronic inflammation. (End of Abstract)

描述（由申请人提供）：动脉粥样硬化是糖尿病患者死亡和残疾的主要原因。糖尿病至少部分通过干扰内皮稳态来发挥其亲动作作用。胰岛素抵抗状态（包括2型糖尿病）与内皮衍生的一氧化氮（NO）和内皮依赖性血管舒张的改善有关，并且内皮功能预测心血管疾病。基础研究表明，胰岛素受体介导的PI-3激酶途径的激活对于正常的内皮一氧化氮合酶（ENOS）功能很重要。最近的研究表明，亚急性，慢性炎症，特别是由IKK？ /NF-KB途径介导的重要作用，在胰岛素抵抗和2型糖尿病的发展中。我们假设IKK？ /NF-KB信号通路的激活有助于糖尿病患者的动脉粥样硬化的发展，部分是通过降低一氧化氮和内皮功能受损的生物利用度。水杨酸酯抑制NF-KB调节蛋白IKK？，下调了NF-KB激活，并且似乎可以改善胰岛素抵抗及其相关的代谢异常。根据以下内容，我们计划确定抑制I [kappa] B激酶[beta]（IKK？）/NF- [Kappa B]，炎症的主要调节剂（salsalate）将恢复2型糖尿病患者的内皮血管舒张。这被认为是TINSAL-T2D（使用Salsalate用于2型糖尿病的靶向炎症）的物质，这是由NIH资助的研究（No.UO1-DK074556）。 Tinsal-T2D的总体目标是确定水杨酸盐是否代表了糖尿病管理的新药物选择。在这项多中心，双掩盖的安慰剂对照试验中，我们将使用salsalate靶向炎症，以研究其对内皮功能和动脉粥样硬化风险的影响。流动介导的，腕（导管）动脉的内皮依赖性血管舒张将通过高分辨率的2型糖尿病患者的高分辨率血管超声检查来测量。此外，内皮功能的变化将被评估为血糖和循环炎性介质以及游离脂肪酸，脂联素和硝基酪氨酸的变化的函数。可以预料，这项投资的发现将发现一种重要的病理生理机制，该机制解释了异常的血管功能，并确定了一种潜在的疗法，以降低2型糖尿病患者患心血管不良事件的风险。这项投资是及时和重要的，因为它可能会提供第一个信息，以表明直接靶向炎症可以改善2型糖尿病患者的内皮功能和动脉粥样硬化风险。这些研究可能提供了一种新的药物结肠策略的初步证据，以治疗或预防与亚急性慢性炎症有关的糖尿病患者或相关胰岛素耐药综合症患者的心血管疾病。（抽象的结尾）