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

• 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
• 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

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发挥其促动脉粥样硬化作用。胰岛素抵抗状态，包括2型糖尿病，与内皮源性一氧化氮（NO）的生物利用度降低和内皮依赖性血管舒张功能受损相关，内皮功能受损可预测心血管事件。基础研究表明，胰岛素受体介导的PI-3激酶通路的激活对于正常内皮型一氧化氮合酶（eNOS）功能是重要的。最近的研究表明，在胰岛素抵抗和2型糖尿病的发展中，亚急性、慢性炎症，特别是由IKK？/NF-κ B通路介导的炎症起着重要作用。我们假设IKK <$/NF-κ B信号通路的激活有助于糖尿病患者动脉粥样硬化的发展，部分原因是降低了一氧化氮的生物利用度并损害了内皮功能。水杨酸盐抑制NF-κ B调节蛋白IKK，下调NF-κ B活化，并似乎改善胰岛素抵抗及其相关的代谢异常。因此，我们计划确定是否抑制I[kappa] B激酶[β]（IKK）/NF-[kappa]B，炎症的主要调节因子，双水杨酸，将恢复2型糖尿病患者的内皮依赖性血管舒张。本研究拟作为TINSAL-T2 D（使用水杨酸治疗2型糖尿病的靶向炎症）的子研究，该研究由NIH资助（编号UO 1-DK 074556）。TINSAL-T2 D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。在这项多中心、双盲、安慰剂对照试验中，我们将使用双水杨酯靶向炎症，研究其对内皮功能和动脉粥样硬化风险的影响。在2型糖尿病患者中，将通过高分辨率血管超声检查测量肱动脉（管道）的血流介导的内皮依赖性血管舒张。此外，内皮功能的变化将作为血小板和循环炎症介质以及游离脂肪酸、脂联素和硝基酪氨酸变化的函数进行评估。预计这项研究的结果将揭示导致血管功能异常的重要病理生理机制，并确定降低2型糖尿病患者心血管不良事件风险的潜在治疗方法。这项研究是及时和重要的，因为它可能提供第一个信息，表明直接靶向炎症可能改善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。(End摘要）