A pilot study of moderate hyperbilirubinemia in type 1 diabetes mellitus

描述（由申请方提供）：拟定的初步研究旨在成为开发诱导中度高胆红素血症以预防1型糖尿病（T1DM）血管并发症的新型治疗策略的第一步。氧化应激，定义为相对于抗氧化剂过量的氧化剂，在很大程度上驱动了T1DM的血管并发症。胆红素，长期以来被认为是代谢废物，现在被认为具有显着的抗氧化性能。除了减少氧化剂，胆红素直接抑制NADPH氧化酶，这是糖尿病血管氧化应激的主要贡献者。因此，提高胆红素水平不仅有可能增加抗氧化能力，而且还可能直接抑制氧化剂的产生。拟议的研究将使用阿扎那韦药物诱导高胆红素血症。阿扎那韦被批准用于治疗艾滋病毒感染。它抑制负责胆红素结合的肝酶，从而清除，导致胆红素水平升高。本研究将获得诱导的中度高胆红素血症对T1DM患者内皮功能、抗氧化能力和氧化应激影响的初步数据。内皮功能是血管内层健康状况的反映。 测量内皮功能可提供有关心血管风险的信息。胆红素水平升高可能通过减轻血管氧化应激而有益于内皮功能。具体目标：目的：探讨1型糖尿病中度高胆红素血症对血管内皮功能影响的可行性。阿扎那韦是一种抑制胆红素结合的药物，将用于诱导中度高胆红素血症。将在阿扎那韦治疗前后测量内皮功能。此外，将测量抗氧化能力和氧化应激的血浆标志物，作为诱导的中度高胆红素血症对1型糖尿病的氧化应激具有有利作用的概念验证。我们将在阿扎那韦400 mg每日一次× 8天的开放标签、单臂干预研究中研究20例T1DM受试者。将在研究第4天和第8天测量胆红素和内皮功能。如果该试验成功，将进行高胆红素血症对T1DM患者内皮功能影响的对照研究。最终的目标是进行一项关于高胆红素血症对1型糖尿病心血管事件影响的大型临床试验。 公共卫生相关性：1型糖尿病（“青少年糖尿病”）有很高的心脏病风险。这项提案希望表明，在1型糖尿病中，通过使用目前可用但尚未被视为糖尿病治疗的药物来降低心脏病的风险是可能的。这种药物的工作原理是，它提高了血液中的胆红素水平，胆红素可以保护心脏和血管免受糖尿病的损害。

DESCRIPTION (provided by applicant): The proposed pilot study aims to be the first step in developing a novel treatment strategy of inducing moderate hyperbilirubinemia for preventing the vascular complications of type 1 diabetes mellitus (T1DM). Oxidative stress, defined as an excess of oxidants relative to antioxidants, in large part drives the vascular complications of T1DM. Bilirubin, long thought of as metabolic waste, is now recognized to have significant antioxidant properties. In addition to reducing oxidants, bilirubin directly inhibits the NADPH oxidase enzyme that is the major contributor to vascular oxidant stress in diabetes. Raising bilirubin levels therefore has the potential to not only increase antioxidant capacity but also directly inhibit oxidant generation. The proposed study will employ the drug atazanavir to induce hyperbilirubinemia. Atazanavir is approved for the treatment of HIV infection. It inhibits the hepatic enzyme responsible for bilirubin conjugation and therefore clearance, resulting in higher bilirubin levels. The proposed study will obtain preliminary data on the effects of induced moderate hyperbilirubinemia on endothelial function, antioxidant capacity, and oxidant stress in T1DM . Endothelial function is a reflection of the health of the inner lining of the blood vessels. Measuring endothelial function provides information about cardiovascular risk. Increased bilirubin levels could plausibly benefit endothelial function by lessening vascular oxidative stress. Specific Aim: To establish the feasibility of studying the change in endothelial function caused by induced moderate hyperbilirubinemia in type 1 diabetes mellitus. Atazanavir, a drug that inhibits bilirubin conjugation, will be used to induce moderate hyperbilirubinemia. Endothelial function will be measured before and after atazanavir therapy. In addition, plasma markers of antioxidant capacity and oxidant stress will be measured as proof-of-concept that induced moderate hyperbilirubinemia has favorable effects on oxidative stress in type 1 diabetes. We will study 20 subjects with T1DM in an open label, single arm intervention study of atazanavir 400 mg once daily x 8 days. Bilirubin and endothelial function will be measured on study days 4 and 8. If this pilot is successful, a controlled study of the effects of hyperbilirubinemia on endothelial function in T1DM would follow. Ultimately the goal is to conduct a large clinical trial of the effect of hyperbilirubinemia on cardiovascular events in type1 diabetes mellitus. PUBLIC HEALTH RELEVANCE: Type 1 diabetes mellitus ('juvenile diabetes') has a high risk of heart disease. This proposal hopes to show that it is possible in type 1 diabetes to reduce the risk of heart disease by using a medicine that is currently available but not yet considered a treatment for diabetes. The way this medicine works is that it raises bilirubin levels in the blood and bilirubin may protect the heart and blood vessels from damage due to diabetes.