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扰乱内皮稳态来发挥其促动脉粥样硬化作用，包括2型糖尿病，与内皮生物利用度降低有关。衍生的一氧化氮（NO）和内皮依赖性血管舒张受损以及内皮功能受损可预测心血管事件。表明胰岛素受体介导的 PI-3 激酶途径的激活对于正常内皮一氧化氮合酶 (eNOS) 功能很重要。最近的研究表明，它对于亚急性、慢性炎症（特别是由 IKK 介导）具有重要作用。 /NF-kB 通路，在胰岛素抵抗和 2 型糖尿病的发展过程中，我们与 IKK 的激活作斗争。 /NF-kB 信号通路有助于糖尿病患者发生动脉粥样硬化，部分原因是降低一氧化氮的生物利用度并损害内皮功能，抑制 NF-kB 调节蛋白 IKK¿ ，下调 NF-κB 激活，并似乎改善胰岛素抵抗及其相关的代谢异常。因此，我们计划确定 Iκ B 激酶 β (IKKK)/NF-κB 的抑制是否是一种作用。炎症的主要调节剂与双水杨酸将恢复 2 型糖尿病患者的内皮依赖性血管舒张功能，这被提议作为 TINSAL-T2D 的子研究（靶向）。 TINSAL-T2D 的总体目标是确定水杨酸盐是否代表糖尿病管理的新药理学选择。在隐蔽的安慰剂对照试验中，我们将使用双水杨酸针对炎症，研究其对内皮功能和血流介导的动脉粥样硬化风险的影响。将通过高分辨率血管超声检查测量 2 型糖尿病患者的肱动脉内皮依赖性血管舒张，此外，将根据血糖和循环炎症介质的变化来评估内皮功能的变化。以及游离脂肪酸、脂联素和硝基酪氨酸预计这项研究的结果将揭示解释血管功能异常的重要病理生理机制并确定潜在的潜在机制。这项研究是及时且重要的，因为它可能提供第一个信息，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。可能为治疗或预防糖尿病或与亚急性慢性炎症相关的胰岛素抵抗综合征患者的心血管疾病提供新的药理学策略的初步证据（摘要结束）。