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

• 批准号: 10321272
• 负责人: DONALD A. MCCLAIN
• 金额: $ 65.97万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-20 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321272
• 关键词: Adoption; Adult; Aftercare; Aging; Alanine Transaminase; Animal Model; Biological Markers; Blood Banks; Blood Donations; Cirrhosis; Clinical; Clinical Trials; Continuous Glucose Monitor; Data; Diabetes Mellitus; Diabetic mouse; Diet; Dietary Iron; Dietary intake; Disease Progression; Dose; Epidemiology; Etiology; Evolution; Fatty Acids; Fatty Liver; Ferritin; Glucose; Healthcare Systems; Hereditary hemochromatosis; Homeostasis; Human; Individual; Inflammation; Inherited; Insulin; Iron; Iron Overload; Link; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Magnetic Resonance Imaging; Measures; Metabolic Pathway; Metabolic syndrome; Modality; Modeling; Non-Insulin-Dependent Diabetes Mellitus; Normal Range; North Carolina; Outcome; Pain; Participant; Pathogenesis; Pathologic; Patients; Persons; Pharmaceutical Preparations; Phenotype; Population; Population Heterogeneity; Prediabetes syndrome; Prevalence; Prevention; Primary carcinoma of the liver cells; Randomized; Red Cross; Research Design; Risk; Risk Factors; Rodent Model; Role; Safety; Sampling; Serum; Target Populations; Testing; Time; Tissues; Transaminases; Universities; Venous blood sampling; Work; aged; beta Thalassemia; blood glucose regulation; cohort; diabetes risk; dietary excess; elastography; fasting glucose; forest; glucose monitor; improved; improved outcome; indexing; insulin sensitivity; intravenous glucose tolerance test; liver inflammation; liver injury; liver stiffness; metabolomics; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; nutrition; pilot trial; prevent; primary endpoint; primary outcome; randomized placebo controlled trial; recruit; secondary outcome; tissue biomarkers; treatment arm; ultrasound

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（T2DM）的风险之间的联系已 在几个不同的人群中展示，通常是糖尿病患病率和 铁蛋白的血清水平，组织铁的标记。重要的是，风险通过正常的整个范围增加 铁蛋白。有令人信服的证据表明，减少铁超负荷铁中铁的有益作用，例如 在遗传性血色素沉着症或β地中海贫血中看到的，但是典型的T2DM和正常数据中的数据 铁蛋白的范围不太清晰。我们已经证明了几只小鼠减少饮食铁的好处 糖尿病的模型，并介绍了人类试验试验的数据，该数据也显示出血糖的改善 放血。然而，剂量响应能力和时间过程尚不清楚。多达60％ T2DM患者也有脂肪肝，这种疾病可以发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。像糖尿病一样，纳什和铁蛋白也是 相关的，但还没有令人信服地解决因果关系和可逆性问题。 假设：我们假设铁有助于T2DM和 纳什（Nash 通过静脉切开术将铁还原为正常较低范围的水平将受益。利益将是 通过改善胰岛素敏感性和胰岛素的改善而表现出来 分泌能力，肝脏损害和炎症指标的降低。 具体目的：我们在Wake Forest和UNC Chapel提出了一项随机的安慰剂对照试验 山丘确定静脉切开术还对T2DM，前糖尿病和前的静脉切除术会产生有益的作用 假定纳什。我们将测试降铁是否会改善：（1）血糖，主要结果为 静脉切开术后6个月的HGBA1C改善，并且随着次要结果的其他措施 和代谢综合征； （2）假定NASH的临床指数，主要是血清转氨酶12个月 静脉切开术后，还通过弹性术以及肝脏僵硬，并； （3）胰岛素敏感性和/或分泌能力。 临床影响：如果在大型和多样的队列中可以证明积极影响，并且更好 剂量反应和治疗阈值的定义，这将定义一系列最佳血清铁蛋白 更狭窄的正常和合理的广泛采用了简单，安全，廉价， T2DM，前糖尿病和NASH的可接受治疗方式（献血） 人体铁储存的人口在较高的正常范围内。