THR-0921 for Cardiovascular Complications of Diabetes

描述（由申请人提供）：项目摘要/摘要：胰岛素介导的葡萄糖处置抵抗现在被认为是葡萄糖耐受个体（非糖尿病患者）最早的异常，最终将发展为2型糖尿病。除了是动脉粥样硬化的危险因素之外，最近的研究已经确定，患有2型糖尿病的患者还表现出血管成形术后再狭窄率增加。我们的初步研究表明，在没有明显高血糖的情况下，胰岛素抵抗与球囊损伤大鼠模型中再狭窄的增强以及炎症的增加（由血管活性氧簇的产生和炎症基因的表达增强确定）有关。此外，胰岛素抵抗与内源性一氧化氮合酶抑制剂不对称二甲基精氨酸（ADMA）的循环水平增加有关，这为加速再狭窄反应提供了另一种机制。THR-0921是一种新型胰岛素增敏化合物，具有强效降糖活性、适度的PPAR-y活性以及抗炎作用。该提案将测试THR-0921在胰岛素抵抗大鼠模型中抑制再狭窄的功效以及其对ADMA水平的影响。因此，我们将使用我们的体内模型来解决这些具体目标：1）扩展我们的初步发现，以确定THR-0921在控制再狭窄中的潜在治疗适用性，特别是在胰岛素抵抗的情况下。2)确定THR-0921降低胰岛素抵抗动物中ADMA水平的疗效。如果SBIR I期结果显示在我们的胰岛素抵抗动物模型中的活性，则SBIR II期研究的目标将是追求THR-0921用于治疗胰岛素抵抗和2型糖尿病的临床开发。目标将是开发一种有效的胰岛素增敏剂，与传统的噻唑烷二酮类药物相比，其对心血管生物学的作用已得到证实，副作用减少。项目叙述：成年后患糖尿病（2型糖尿病）的人通常有相关的疾病，如肥胖，这会增加他们患冠心病的风险。不幸的是，通常用于治疗2型糖尿病的最新药物具有不良副作用，进一步增加了心脏病的风险。目前的研究旨在评估这类新药，不仅似乎具有较少的心脏相关副作用，而且可能有助于减少用于治疗冠心病的某些外科手术引起的并发症。

DESCRIPTION (provided by applicant): Project Summary/Abstract: Resistance to insulin-mediated glucose disposal is now recognized as the earliest abnormality in glucose tolerant individuals (nondiabetics) who will eventually develop type 2 diabetes. In addition to being a risk factor for atherosclerosis, recent studies have established that patients with type 2 diabetes also demonstrate increased rate of restenosis after angioplasty. Our preliminary studies indicate that insulin resistance, in the absence of frank hyperglycemia, is associated with enhanced restenosis in a rat model of balloon injury, as well as increased inflammation as determined by vascular production of reactive oxygen species and enhanced expression of inflammatory genes. Moreover, insulin resistance is associated with increased circulating levels of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine (ADMA), providing another mechanism for the accelerated restenotic response. THR-0921 is a novel insulin sensitizing compound that has potent glucose-lowering activity, modest PPAR-y activity, as well as anti-inflammatory actions. This proposal will test the efficacy of THR-0921 to inhibit restenosis in a rat model of insulin resistance as well as its effects on ADMA levels. Accordingly, we will use our in vivo model to address these specific aims: 1) To expand upon our initial findings to determine the potential therapeutic applicability of THR-0921 in the control of restenosis, particularly in the setting of insulin resistance. 2) To determine the efficacy of THR-0921 to reduce ADMA levels in insulin resistant animals. If the SBIR phase I results show activity in our animal model of insulin resistance, the goal in an SBIR phase II study will be to pursue clinical development of THR-0921 for the treatment of insulin resistance and type 2 diabetes. The goal will be to develop a potent insulin sensitizer with demonstrated effects on cardiovascular biology that has a reduced side effect profile compared with traditional thiazolidinediones. Project Narrative: People who develop diabetes as adults (type 2 diabetes) often have related conditions such as obesity that increase their risk for developing coronary heart disease. Unfortunately, the newest drugs commonly used to treat type 2 diabetes have undesired side effects that further increase the risk of heart disease. The current study is designed to evaluate a new drug in this class that not only appears to have fewer heart-related side effects, but also may help reduce complications that arise from certain surgical procedures used to treat coronary heart disease.