Iron Reduction for the Treatment of Diabetes and Nonalcoholic Fatty Liver Disease

铁还原治疗糖尿病和非酒精性脂肪肝

基本信息

项目摘要

Background: A link between tissue iron and the risk of type 2 diabetes mellitus (T2DM) has been demonstrated across several diverse populations, usually as a relationship between diabetes prevalence and serum levels of ferritin, a marker of tissue iron. Importantly, risk increases through the entire range of normal ferritin. There is convincing evidence of beneficial effects of reducing iron in pathologic iron overload such as that seen in hereditary hemochromatosis or beta thalassemia, but the data in typical T2DM and in the normal ranges of ferritin are less clear-cut. We have demonstrated a benefit of dietary iron reduction in several mouse models of diabetes, and present data from a pilot trial in humans that also shows improvement of glycemia with phlebotomy. Dose responsiveness and time course of that benefit, however, are not known. Up to 60% of people with T2DM also have fatty liver, a condition that can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis, liver failure and/or hepatocellular carcinoma. Like diabetes, NASH and ferritin are also associated, but the same questions of causality and reversibility have not been convincingly resolved. Hypothesis: We hypothesize that iron contributes to the pathogenesis and progression of T2DM and NASH, and that individuals with tissue iron levels, as reflected by serum ferritin, in the upper ranges of normal will benefit from reducing iron by phlebotomy to levels in the lower ranges of normal. The benefit will be manifest by improvements in glycemia resulting from improvements in both insulin sensitivity and insulin secretory capacity, and decreases in indices of liver damage and inflammation in those individuals with NASH. Specific Aims: We propose a randomized, placebo-controlled trial at Wake Forest and UNC Chapel Hill to determine if there is a beneficial effect of iron reduction by phlebotomy on T2DM, prediabetes, and presumed NASH. We will test if iron reduction will improve: (1) Glycemia, with a primary outcome of improvement in HgbA1C 6 months after phlebotomy, and as secondary outcomes other measures of glycemia and Metabolic Syndrome; (2) Clinical indices of presumed NASH, primarily serum transaminases 12 months after phlebotomy, and also liver stiffness by elastography, and; (3) Insulin sensitivity and/or secretory capacity. Clinical impact: If positive effects could be demonstrated in a large and diverse cohort, with better definition of dose-responsiveness and treatment thresholds, this would define a range of optimal serum ferritin much narrower that the broad range of normal and justify widespread adoption of a simple, safe, inexpensive, and acceptable treatment modality (blood donation) for T2DM, prediabetes, and NASH in the large fraction of the population with body iron stores in the higher range of normal.
背景:组织铁与2型糖尿病(T2 DM)风险之间的联系已经被证实。 在几个不同的人群中证明,通常是糖尿病患病率和 血清铁蛋白水平,一种组织铁的标志物。重要的是,风险在整个正常范围内增加, 铁蛋白。有令人信服的证据表明,减少铁在病理性铁过载中的有益作用, 在遗传性血色病或β地中海贫血中观察到,但在典型T2 DM和正常T2 DM中的数据 铁蛋白的范围不太明确。我们已经在几只小鼠中证明了饮食铁减少的益处 糖尿病模型,并提供了来自人类试点试验的数据,该试验也显示了糖尿病的改善。 静脉切开术然而,这种益处的剂量反应性和时间过程尚不清楚。高达60%的 2型糖尿病患者还患有脂肪肝,这种疾病可进展为非酒精性脂肪性肝炎(NASH) 和肝硬化、肝衰竭和/或肝细胞癌。与糖尿病一样,NASH和铁蛋白也是 这些问题是相互关联的,但因果关系和可逆性问题尚未得到令人信服的解决。 假设:我们假设铁有助于T2 DM的发病机制和进展, NASH,并且组织铁水平的个体,如血清铁蛋白所反映的,在正常范围的上限内, 将受益于通过放血将铁减少到正常范围的较低水平。受益的将是 通过胰岛素敏感性和胰岛素敏感性两者的改善导致的胰岛素抵抗的改善来表现。 在那些患有NASH的个体中,降低了分泌能力,并降低了肝损伤和炎症指数。 具体目标:我们建议在维克森林和维克查普尔进行一项随机、安慰剂对照试验 Hill,以确定通过静脉切开术减少铁对T2 DM、前驱糖尿病和 推测为NASH。我们将测试铁减少是否会改善:(1)血糖,主要结局为 静脉切开术后6个月HgbA 1C的改善,以及作为次要结局的其他指标 和代谢综合征;(2)假定NASH的临床指标,主要是12个月的血清转氨酶 静脉切开术后,以及弹性成像的肝硬度,和(3)胰岛素敏感性和/或分泌能力。 临床影响:如果积极的效果可以在一个大的和多样化的队列中得到证明, 剂量反应性和治疗阈值的定义,这将定义最佳血清铁蛋白的范围 窄得多的是,广泛的正常和合理的广泛采用一个简单的,安全的,便宜的, 和可接受的T2 DM、前驱糖尿病和NASH治疗方式(献血), 体内铁含量在正常范围内的人群。

项目成果

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DONALD A. MCCLAIN其他文献

DONALD A. MCCLAIN的其他文献

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{{ truncateString('DONALD A. MCCLAIN', 18)}}的其他基金

Administrative Supplement for Quality Assurance/Quality Control
质量保证/质量控制行政补充
  • 批准号:
    10261703
  • 财政年份:
    2021
  • 资助金额:
    $ 65.97万
  • 项目类别:
Mechanism of Integrative Metabolic Regulation by Iron and Hypoxia
铁和缺氧综合代谢调节机制
  • 批准号:
    10514581
  • 财政年份:
    2020
  • 资助金额:
    $ 65.97万
  • 项目类别:
Mechanism of Integrative Metabolic Regulation by Iron and Hypoxia
铁和缺氧综合代谢调节机制
  • 批准号:
    10293553
  • 财政年份:
    2020
  • 资助金额:
    $ 65.97万
  • 项目类别:
North Carolina Diabetes Research Center
北卡罗来纳州糖尿病研究中心
  • 批准号:
    10609094
  • 财政年份:
    2020
  • 资助金额:
    $ 65.97万
  • 项目类别:
North Carolina Diabetes Research Center
北卡罗来纳州糖尿病研究中心
  • 批准号:
    10290723
  • 财政年份:
    2020
  • 资助金额:
    $ 65.97万
  • 项目类别:
North Carolina Diabetes Research Center
北卡罗来纳州糖尿病研究中心
  • 批准号:
    10382306
  • 财政年份:
    2020
  • 资助金额:
    $ 65.97万
  • 项目类别:
Mechanism of Integrative Metabolic Regulation by Iron and Hypoxia
铁和缺氧综合代谢调节机制
  • 批准号:
    10004944
  • 财政年份:
    2020
  • 资助金额:
    $ 65.97万
  • 项目类别:
North Carolina Diabetes Research Center
北卡罗来纳州糖尿病研究中心
  • 批准号:
    10609095
  • 财政年份:
    2020
  • 资助金额:
    $ 65.97万
  • 项目类别:
North Carolina Diabetes Research Center
北卡罗来纳州糖尿病研究中心
  • 批准号:
    10382307
  • 财政年份:
    2020
  • 资助金额:
    $ 65.97万
  • 项目类别:
Wake Forest Clinical and Translational Science Award
维克森林临床和转化科学奖
  • 批准号:
    10204146
  • 财政年份:
    2015
  • 资助金额:
    $ 65.97万
  • 项目类别:

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