Prevention of Diabetic Neuropathy with ACE Inhibitors

描述（由申请人提供）：我们的研究目的是确定链脲佐菌素诱导的糖尿病大鼠（1型糖尿病动物模型）、Zucker糖尿病脂肪大鼠（2型糖尿病动物模型）或Zucker肥胖大鼠（糖尿病前期/代谢综合征动物模型）是否使用依那普利(血管紧张素转换酶（ACE）抑制剂、AVE7688（血管肽酶抑制剂）或西格列汀（二肽基肽酶IV （DPP-IV）抑制剂）治疗。预防/逆转糖尿病性神经病变（DN）的发生/进展。用ACE抑制剂治疗糖尿病患者是治疗肾脏和心血管疾病的一种常见形式。然而，对于ACE抑制剂治疗DN的潜在益处还缺乏了解。ACE抑制剂已被证明具有抗氧化和神经保护特性；而

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.