Prevention of Diabetic Neuropathy with ACE Inhibitors

使用 ACE 抑制剂预防糖尿病神经病变

基本信息

批准号：
7637375
负责人：
Mark A. Yorek
金额：
$ 26.78万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7637375
关键词：
3-nitrotyrosine Acetylcholine Address Adverse effects Angiotensin II Receptor Angiotensin Receptor Angiotensin-Converting Enzyme Inhibitors Animal Model Antioxidants Attenuated Blood Vessels Blood flow Bradykinin C-Type Natriuretic Peptide Calcitonin Gene-Related Peptide Cardiovascular Diseases Clinical Clinical Research Clinical Trials Development Diabetes Mellitus Diabetic Neuropathies Dipeptidyl-Peptidase IV Disease Drug usage Enalapril Endothelium Enzyme Inhibition Epidermis Filament Functional disorder Future Goals Human Impairment Insulin-Dependent Diabetes Mellitus Kidney Kidney Diseases Knowledge Measurement Mediating Mediator of activation protein Metabolic syndrome Modeling Motor Natriuretic Peptides Neprilysin Nerve Nerve Fibers Neural Conduction Neuropathy Neuropeptides Nitric Oxide Nociception Non-Insulin-Dependent Diabetes Mellitus Obesity Oxidative Stress Patients Peptide Hydrolases Peptides Peptidyl-Dipeptidase A Peripheral Peripheral Vascular Diseases Peroxonitrite Pharmaceutical Preparations Pharmacodynamics Prediabetes syndrome Prevention Property Rat-1 Rattus Relaxation Renal Glycosuria Research Role Streptozocin Superoxides Testing Tissues United States Vascular Endothelium-Dependent Relaxation Vasodilation Vasodilator Agents Work Zucker Rats afferent nerve arteriole base design diabetic diabetic rat effective therapy efficacy testing enzyme activity glucagon-like peptide 1 improved inhibitor/antagonist insulin sensitivity novel strategies polypeptide C preclinical study prevent primary outcome public health relevance relating to nervous system sciatic nerve secondary outcome therapy design type I and type II diabetes

项目摘要

DESCRIPTION (provided by applicant): The goal of our studies is to determine whether treatment of streptozotocin-induced diabetic rats, an animal model for type 1 diabetes, Zucker Diabetic Fatty (ZDF) rats, an animal model for type 2 diabetes, or Zucker obese rats, an animal model for pre-diabetes/metabolic syndrome with Enalapril, an angiotensin converting enzyme (ACE) inhibitor, AVE7688, a vasopeptidase inhibitor, or Sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, prevents/reverses the development/progression of diabetic neuropathy (DN). Treatment of diabetes patients with ACE inhibitors is a common form of treatment for renal and cardiovascular disease. However, there is a lack of knowledge about the potential benefits of ACE inhibitor treatment for DN. ACE inhibitors have been shown to have antioxidant and neuroprotective properties; whereas vasopeptidase inhibitors block both ACE and neutral endopeptidase (NEP) activity. We also have evidence that Sitagliptin, a drug used to increase insulin sensitivity and treat type 2 diabetes, may also inhibit NEP. NEP degrades natriuretic peptides as well as neuropeptides such as calcitonin gene-related peptide (CGRP) and bradykinin. Our working hypothesis is that vascular dysfunction contributes significantly to DN and that successful therapies for DN must protect the vasculature. We have shown that diabetes and obesity alters the activity of vasodilators in epineurial arterioles including nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and CGRP. This likely causes an impairment of blood flow to the nerve and contributes to DN. Based on recent studies we hypothesize the C-type natriuretic peptide (CNP) functions as EDHF in epineurial arterioles. CNP causes vasodilation of epineurial arterioles and CNP activity/expression is decreased by diabetes. Therefore, we propose that treating rat models of type 1 and type 2 diabetes as well as obesity with Enalapril, AVE7688 or Sitagliptin will attenuate the development/progression of DN by: 1) preventing oxidative stress in vascular tissue thereby protecting the activity of NO, 2) preventing the loss of CNP and protecting its bioactivity, and 3) protecting sensory nerves and the availability and function of CGRP. If successful, these studies could provide a rationale for designing clinical studies to further test the efficacy of ACE and/or vasopeptidase inhibitor treatment in human DN. PUBLIC HEALTH RELEVANCE: After many years of research that is not an effective treatment for diabetic neuropathy. The goal of this study is to test the efficacy in pre-clinical studies of three classes of drugs on diabetic vascular and neural disease. Our working hypothesis is that vascular dysfunction contributes significantly to diabetic neuropathy and that successful therapies must protect the vasculature. If successful, these studies could provide a rationale for designing clinical studies to further test the efficacy of angiotensin converting enzyme and/or vasopeptidase inhibitor treatment in human diabetic neuropathy.

描述（由申请人提供）：我们的研究的目的是确定链蛋白酶诱导的糖尿病大鼠的治疗是一种用于1型糖尿病的动物模型，Zucker糖尿病脂肪（ZDF）大鼠是一种2型糖尿病的动物模型，用于2型糖尿病的动物模型，还是Zucker肥胖大鼠，是针对前糖尿病/糖尿病的动物模型，与抗糖尿病/隔离剂的动物模型，and依孕剂构成代替剂，促成剂量，烯酸盐剂，促成剂量，烯酸酯剂，促成剂量，氧化剂。（ACE）抑制剂AVE7688，血管肽酶抑制剂或二肽基肽酶IV（DPP-IV）抑制剂的西格列汀，可防止/逆转糖尿病性新疗法（DN）的发育/进展。用ACE抑制剂治疗糖尿病患者是肾脏和心血管疾病的一种常见治疗形式。但是，缺乏关于ACE抑制剂治疗DN的潜在益处的知识。 ACE抑制剂已被证明具有抗氧化剂和神经保护特性。然而血管肽酶抑制剂可阻止ACE和中性内肽酶（NEP）活性。我们也是有证据表明，西他列汀是一种用于提高胰岛素敏感性和治疗2型糖尿病的药物，也可能抑制NEP。 NEP降解了亚钠肽以及神经肽，例如降钙素基因相关的肽（CGRP）和松曲蛋白。我们的工作假设是，血管功能障碍对DN产生了重大贡献，而DN的成功疗法必须保护脉管系统。我们已经表明，糖尿病和肥胖改变了包括一氧化氮（NO），内皮衍生的超极化因子（EDHF）和CGRP（包括一氧化氮）和CGRP的血管扩张剂的活性。这可能导致血液流向神经的流动损害并导致DN。基于最近的研究，我们假设C型含有纳地酸肽（CNP）在肾上腺动脉中充当EDHF。 CNP导致糖尿病的血管舒张和CNP活性/表达降低。因此，我们建议治疗1型和2型糖尿病的大鼠模型，以及用依那普利，AVE7688或西他列汀将减弱DN的发育/进展：1）预防氧化应激在血管组织中，从而保护NO的活性，2）防止CNP丧失并保护其生物活性，3）保护感觉神经以及CGRP的可用性和功能。如果成功，这些研究可以为设计临床研究提供基本原理，以进一步测试ACE和/或血管肽酶抑制剂在人DN中的疗效。公共卫生相关性：经过多年的研究，这不是对糖尿病神经病的有效治疗方法。这项研究的目的是测试三类药物对糖尿病血管和神经疾病的临床研究的功效。我们的工作假设是，血管功能障碍对糖尿病神经病产生了重大贡献，并且成功的疗法必须保护血管系统。如果成功，这些研究可以为设计临床研究提供基本原理，以进一步测试人类糖尿病神经病中的血管紧张素转化酶和/或血管肽酶抑制剂治疗的疗效。