Insulin Resistance and Vascular Complications in Obesity and Type 2 Diabetes

描述（由申请人提供）： 导致2型糖尿病风险增加的肥胖、胰岛素抵抗和相关代谢异常以“代谢综合征”一词最为人所知。肥胖和 2 型糖尿病在美国和退伍军人事务医疗保健系统服务的患者中已达到流行水平。这些疾病导致发病率增加、生活质量下降以及医疗保健费用增加。目前，对于与肥胖和2型糖尿病相关的并发症还没有有效的治疗方法。尽管研究已经提出了改善胰岛素敏感性的新疗法，但这种方法只能延缓并发症的发生。由于并发症最终是导致 2 型糖尿病患者发病率增加和生活质量差的原因，因此迫切需要开发能够预防或减少其影响的疗法。我们提出的研究将为 Ilepatril 的功效和机制提供临床前证据，Ilepatril 是一种血管肽酶抑制剂，可同时阻断血管紧张素转换酶 (ACE) 和中性肽链内切酶 (NEP) 活性，治疗胰岛素抵抗以及与肥胖和 2 型糖尿病相关的血管并发症。 在过去 5 年中，我们在确定 ACE 和 NEP 在与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。我们还对高脂肪饮食/低剂量链脲佐菌素治疗的大鼠（一种有趣的 2 型糖尿病模型）的血管和神经并发症进行了表征。在本提案中，我们将扩展这些研究并检验 Ilepatril 在体内治疗肥胖和/或逆转由肥胖和 2 型糖尿病引起的胰岛素抵抗和血管并发症的能力。要探讨的中心假设是，肥胖和 2 型糖尿病上调对胰岛素抵抗敏感的组织中 ACE 和 NEP 的表达/活性，并且容易出现与肥胖和糖尿病相关的并发症，导致糖耐量受损和血管功能障碍。我们建议，通过以保护血管功能为目标，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，保护血管活性肽免于降解，从而改善血管功能，2) 改善整个动物的葡萄糖利用率，3) 改善骨骼肌的血流，从而改善胰岛素作用和葡萄糖摄取。我们认为，肥胖大鼠在高血糖（2型糖尿病）发作后的治疗效果会较差，可能需要更全面、更积极的治疗策略来减少并发症的影响。具体目标： 目标 1：确定用 Ilepatril 治疗饮食诱导的肥胖大鼠是否通过减少氧化应激和保护血管活性肽，比单独阻断 ACE 或 NEP 的单一疗法更大程度地改善胰岛素敏感性和腓肠肌和比目鱼肌供给动脉的血管功能障碍。目标 2：确定 2 型糖尿病是否会因较高水平的氧化应激和/或血管活性肽的降解而降低 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.