Iron reduction by phlebotomy for the prevention and treatment of type 2 diabetes

描述（由申请人提供）：本申请是根据PA-09-133“糖尿病、内分泌和代谢疾病的试点和可行性临床研究赠款”提出的。“这将是西南/西部山区CTSA联盟、犹他州（母站）、科罗拉多和新墨西哥州大学成员之间的合作努力。该试验是一种新的应用于人类的安全辅助治疗2型糖尿病和前驱糖尿病，是由我们在动物模型中开发和验证的：放血减少铁储存。 一般认为，暴饮暴食主要是通过热量过剩引起糖尿病的风险。然而，越来越多的证据表明，饮食中的特定成分也可能带来风险。例如，大量流行病学和实验研究表明，过量的铁与糖尿病风险密切相关。我们在动物模型中的数据，在一个小的人类样本中验证，表明饮食铁超载的受试者的铁耗竭应该是有益的糖尿病风险通过两个独立的机制，赋予增加胰岛素分泌能力，同时增加胰岛素敏感性。我们将通过降低一组接受二甲双胍和/或DPP-4抑制剂治疗的糖耐量受损和糖尿病患者的铁储备来检验这一假设。将招募处于正常铁蛋白最高四分位数且无已知继发性升高原因的受试者，并将献血直至铁蛋白福尔斯降至正常的最低四分位数。他们将在胰岛素分泌能力、胰岛素敏感性、葡萄糖代谢和代谢综合征标志物的测量前后进行评估。 希望这个有限的试验能提供数据来指导未来的试验，以确定这种新的辅助治疗的剂量反应性、持续时间和普遍性。 治疗糖尿病前期和2型糖尿病此外，我们希望展示CTSA联盟在快速将生物医学研究的最新发现转化为有用的临床发现方面的潜在力量。 公共卫生相关性：该提案将测试一种安全，简单，甚至对社会有益的治疗方法，献血，用于一种正在成为世界性流行病的疾病。虽然我们承认糖尿病是一种具有许多促成因素的异质性疾病，并且目前的方案仅针对铁过载的个体（任意定义为 最高四分位数，即该人群的25%），流行病学数据表明对糖尿病患者的一般人群的影响可能是巨大的。

DESCRIPTION (provided by applicant): This application is being made in response to PA-09-133, "Pilot and Feasibility Clinical Research Grants in Diabetes, Endocrine and Metabolic Diseases." It will be a collaborative effort among the members of the Southwest/MountainWest CTSA Consortium, the Universities of Utah (parent site), Colorado, and New Mexico. The trial is a novel application to humans of a safe adjunct treatment for type 2 diabetes and prediabetes that was developed and validated by us in animal models: Phlebotomy to reduce iron stores. It is generally assumed that overeating engenders diabetes risk principally through caloric excess. There is increasing evidence, however, that specific components of the diet may also impart risk. Excess iron, for example, has been shown in numerous epidemiologic and experimental studies to be strongly associated with diabetes risk. Our data in animal models, validated in a small human sample, suggest that iron depletion of subjects with dietary iron overload should be beneficial to diabetes risk through two independent mechanisms, conferring increased insulin secretory capacity while at the same time increasing insulin sensitivity. We will test this hypothesis by lowering iron stores in a cohort of individuals with impaired glucose tolerance and diabetes controlled on metformin and/or DPP-4 inhibitor therapy. Subjects will be recruited who are in the highest quartile of normal ferritin with no known cause for secondary elevation, and will donate blood until ferritin falls to the lowest quartile of normal. They will be assessed befoe and after for measures of insulin secretory capacity, insulin sensitivity, glucose metabolism, and markers of metabolic syndrome. It is hoped that this limited trial will provide data to guide futue trials to establish dose- responsiveness, duration, and universality for this novel adjunct therapy for prediabetes and type 2 diabetes. In addition, we hope to demonstrate the potential power of the CTSA consortium in rapidly translating the latest findings in biomedical research into useful clinical findings. PUBLIC HEALTH RELEVANCE: The proposal will test a safe, simple, and even societally beneficial treatment, blood donation, for a disease that is becoming a worldwide epidemic. While we acknowledge that diabetes is a heterogeneous disease with many contributing factors, and that the current protocol only addresses individuals with iron overload (arbitrarily defined as the top quartile, i.e. 25% of that population), epidemiologic data suggest the impact on the general population of diabetics is could be substantial.