Insulin Resistance and Vascular Complications in Obesity and Type 2 Diabetes

肥胖和 2 型糖尿病中的胰岛素抵抗和血管并发症

• 批准号: 8698322
• 负责人: Mark A. Yorek
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698322
• 关键词: Address; Affect; Amputation; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arteries; Biological Preservation; Blood Vessels; Blood flow; Bradykinin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Clinical Research; Development; Diabetes Mellitus; Diet; Disease Progression; Dose; Enkephalins; Epidemic; Family; Fat-Restricted Diet; Fatty acid glycerol esters; Functional disorder; Gastrocnemius Muscle; Glucose; Health Care Costs; Healthcare Systems; Hyperglycemia; Inflammation; Insulin; Insulin Resistance; Intervention; Kidney Diseases; Link; Metabolic; Metabolic syndrome; Modeling; Morbidity - disease rate; Muscle; Natriuretic Peptides; Neprilysin; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Oxidative Stress; Pathology; Patients; Peptide Hydrolases; Peptides; Peptidyl-Dipeptidase A; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Prediabetes syndrome; Protease Inhibitor; Quality of life; Rattus; Risk; Role; Skeletal Muscle; Soleus Muscle; Streptozocin; Substance P; Thrombosis; Tissues; Treatment Efficacy; United States; Vascular Diseases; Vascular remodeling; Veterans; diabetic patient; diabetic rat; effective therapy; feeding; glucose uptake; impaired glucose tolerance; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; interest; mortality; obesity treatment; pre-clinical; prevent; relating to nervous system; therapy development; treatment strategy

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.

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型糖尿病的发展风险增加，这是“代谢综合征”一词最著名的。肥胖和2型糖尿病已经在美国和退伍军人事务医疗保健系统服务的患者中达到流行水平。这些条件负责增加发病率，减少生活质量以及增加医疗保健成本。当前，与肥胖和2型糖尿病相关的并发症没有有效的治疗方法。即使研究导致了提高胰岛素敏感性的新疗法，这种方法只会延迟并发症的发作。由于并发症最终导致2型糖尿病患者的发病率和生活质量较差，因此迫切需要开发可以预防或减少其影响的疗法。我们提出的研究将提供临床前的证据，以证明伊利帕里尔的机制（一种血管肽酶抑制剂，同时阻止血管紧张素转化酶（ACE）和中性内肽酶（NEP）活性，治疗胰岛素抵抗和胰岛素抵抗和与肥胖症的血管并透射率和2个透射蛋白相关的血管。 在过去的五年中，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发展中的作用方面取得了重大进展。我们还表征了高脂肪饮食/低剂量链蛋白酶治疗的大鼠的血管和神经并发症，这是2型糖尿病的有趣模型。在本提案中，我们将扩展这些研究，并检查叶骨充当肥胖症和/或反向胰岛素抵抗和由肥胖和2型糖尿病引起的胰岛素耐药性和血管并发症的能力。要探讨的中心假设是，肥胖和2型糖尿病在对胰岛素抵抗敏感的组织中上调ACE和NEP的表达/活性，对与肥胖和糖尿病有关的并发症易于引起葡萄糖耐量和血管功能障碍的并发症。我们建议，通过靶向维护饮食诱导的肥胖大鼠的血管功能治疗叶叶治疗将：1）减少血管组织中的氧化应激，并保护血管活性肽免受降解，从而降解血管功能改善，2）改善整个动物的葡萄糖利用率，以及3）改善骨骼胰岛素的血液流动，并改善了胰岛素的动作。我们认为，高血糖（2型糖尿病）发作后肥胖大鼠的治疗效果较低，可能需要更全面，更积极的治疗策略来减少并发症的影响。特定目标：目标1：确定饮食诱导的肥胖大鼠的治疗是否可以通过减少氧化应激和比单独的单独的单纯疗法来更大程度地保护抗氧化应激和保护血管活性肽，从而改善胃肠痛和比索鲁斯肌肉的进料动脉中的胰岛素敏感性和血管功能障碍。目标2：确定2型糖尿病是否由于较高水平的氧化应激和/O降解血管活性肽而降低了叶骨治疗的益处。