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

描述(申请人提供)：本申请是针对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资助”而提出的。这将是西南/西部山区CTSA联盟、犹他大学(母校)、科罗拉多州和新墨西哥州大学之间的合作努力。这项试验是我们开发并在动物模型中验证的一种治疗2型糖尿病和糖尿病前期的安全辅助治疗方法在人类中的新应用：静脉切开术减少铁储存。一般认为，暴饮暴食主要是通过卡路里过量导致患糖尿病的风险。然而，越来越多的证据表明，饮食中的特定成分也可能会带来风险。例如，许多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得到验证，表明饮食中铁超载的受试者的铁缺乏应该通过两种独立的机制有益于糖尿病风险，即增加胰岛素分泌能力，同时提高胰岛素敏感性。我们将通过降低糖耐量受损和糖尿病患者队列中的铁储存来验证这一假设，这些患者接受二甲双胍和/或DPP-4抑制剂治疗。受试者将被招募，他们的铁蛋白水平处于正常水平的最高四分位数，没有已知的继发性升高原因，并将献血，直到铁蛋白下降到正常水平的最低四分位数。他们将在治疗前和治疗后接受胰岛素分泌能力、胰岛素敏感性、葡萄糖代谢和代谢综合征标志物的评估。希望这项有限的试验将提供数据来指导未来的试验，以建立这种新的辅助疗法的剂量-反应、持续时间和普遍性。 适用于糖尿病前期和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。

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.