Insulin Resistance and Vascular Complications in Obesity and Type 2 Diabetes

描述（由申请人提供）： 肥胖、胰岛素抵抗和相关的代谢异常导致2型糖尿病发展风险增加，最为人所知的是术语“代谢综合征”。肥胖和2型糖尿病在美国和退伍军人事务部医疗保健系统服务的患者中已经达到流行病水平。这些情况导致发病率增加，生活质量下降，医疗保健费用增加。目前，对于肥胖和2型糖尿病相关的并发症没有有效的治疗方法。尽管研究已经导致了新的治疗方法来改善胰岛素敏感性，但这种方法只能延迟并发症的发生。由于并发症最终导致2型糖尿病患者发病率增加和生活质量差，因此迫切需要开发可以预防或减少其影响的治疗方法。我们提出的研究将提供临床前证据的有效性和洞察力的机制Ilepatril，血管肽酶抑制剂，同时阻断血管紧张素转换酶（ACE）和中性内肽酶（NEP）的活动，治疗胰岛素抵抗和血管并发症与肥胖和2型糖尿病。 在过去的5年中，我们在确定ACE和NEP在肥胖和糖尿病相关的血管和神经并发症的发展中的作用方面取得了重大进展。我们还描述了高脂饮食/低剂量链脲佐菌素治疗的大鼠的血管和神经并发症，这是一种有趣的2型糖尿病模型。在目前的建议中，我们将扩展这些研究，并检查Ilepatril作为肥胖症和/或逆转胰岛素抵抗和肥胖症和2型糖尿病引起的血管并发症的治疗在体内的能力。待探讨的中心假设是肥胖和2型糖尿病上调对胰岛素抵抗敏感的组织中的ACE和NEP表达/活性，并且易于发生与肥胖和糖尿病相关的并发症，导致葡萄糖耐量受损和血管功能障碍。我们提出，通过靶向保护血管功能，Ilepatril治疗饮食诱导的肥胖大鼠将：1）减少血管组织中的氧化应激并保护血管活性肽免于降解，从而改善血管功能，2）改善整个动物中的葡萄糖利用，和3）改善骨骼肌中的血流，从而改善胰岛素作用和葡萄糖摄取。我们认为，在高血糖（2型糖尿病）发作后治疗肥胖大鼠的效果较差，可能需要更全面和积极的治疗策略来减少并发症的影响。具体目标：目标1：确定与单独阻断ACE或NEP的单药治疗相比，用Ilepatril治疗饮食诱导的肥胖大鼠是否通过降低氧化应激和保护血管活性肽在更大程度上改善腓肠肌和比目鱼肌供血动脉中的胰岛素敏感性和血管功能障碍。目标二：确定2型糖尿病是否由于较高水平的氧化应激和/或血管活性肽的降解而降低了Ilepatril治疗的益处。

DESCRIPTION (provided by applicant): Obesity, insulin resistance and associated metabolic abnormalities leading to increased risk of development of type 2 diabetes is best known by the term "metabolic syndrome". Obesity and type 2 diabetes have reached epidemic levels in the United States and patients served by the Veterans Affairs Health Care System. These conditions are responsible for increased morbidity, reduced quality of life, and increased health care costs. Currently, there is no effective treatmen for the complications associated with obesity and type 2 diabetes. Even though studies have led to new therapies to improve insulin sensitivity this approach only delays the onset of complications. Since complications are ultimately responsible for the increased morbidity and poor quality of life in patients with type 2 diabetes there is an urgent need for development of therapies that can prevent or reduce their impact. Our proposed studies will provide preclinical evidence of efficacy and insight to mechanisms of Ilepatril, a vasopeptidase inhibitor that simultaneously blocks angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) activities, treatment for insulin resistance and vascular complications associated with obesity and type 2 diabetes. In the last 5 years we made significant progress in determining the role of ACE and NEP in the development of vascular and neural complications associated with obesity and diabetes. We have also characterized the vascular and neural complications in the high fat diet/low dose streptozotocin treated rat, an interesting model for type 2 diabetes. In the present proposal we will extend these studies and examine the ability of Ilepatril to act as a treatment fo obesity and/or reverse insulin resistance and vascular complications caused by obesity and type 2 diabetes in vivo. The central hypothesis to be explored is that obesity and type 2 diabetes up-regulate ACE and NEP expression/activity in tissues sensitive to insulin resistance and prone for complications related to obesity and diabetes leading to impaired glucose tolerance and vascular dysfunction. We propose that by targeting preservation of vascular function Ilepatril treatment of diet induced obese rats will: 1) reduce oxidative stress in vascular tissue and protect vasoactive peptides from degradation leading to improved vascular function, 2) improve glucose utilization in the whole animal, and 3) improve blood flow in skeletal muscle thereby improving insulin action and glucose uptake. We believe that treatment of obese rats after the onset of hyperglycemia (type 2 diabetes) will be less effective and may require a more comprehensive and aggressive treatment strategy to reduce the impact of complications. Specific Objectives: Objective 1: Determine whether treatment of diet induced obese rats with Ilepatril improves insulin sensitivity and vascular dysfunction in feed arteries of gastrocnemius and soleus muscle by reducing oxidative stress and protecting vasoactive peptides to a greater extent than monotherapies that block ACE or NEP alone. Objective 2: Determine whether type 2 diabetes reduces the benefits of Ilepatril treatment due to higher levels of oxidative stress and/o degradation of vasoactive peptides.