IRON AND METABOLISM: ALTERED FUEL OXIDATION AND MITOCHONDRIAL DYSFUNCTION

铁和新陈代谢：改变燃料氧化和线粒体功能障碍

• 批准号: 7656147
• 负责人: DONALD A. MCCLAIN
• 金额: $ 43.86万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656147
• 关键词: Adipocytes; Adverse effects; Animal Model; Beta Cell; Blood; Body mass index; Cardiovascular Diseases; Cells; Data; Defect; Diabetes Mellitus; Diabetes prevention; Diabetic mouse; Diet; Dietary Iron; Disease; Dose; Down-Regulation; Engineering; Etiology; Exhibits; Failure; Fatty acid glycerol esters; Gene Deletion; Glucose; Hemochromatosis; Hepatic; Hereditary Disease; Hereditary hemochromatosis; Hormones; Human; Individual; Insulin; Insulin Resistance; Intake; Intestines; Iron; Iron Overload; Lead; Leptin; Lipids; Mediating; Metabolic; Metabolic syndrome; Metabolism; Metals; Mitochondria; Modeling; Mus; Muscle; Mutate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Oxidative Stress; Phenotype; Phosphotransferases; Play; Poison; Predisposition; Principal Investigator; Production; Regulation; Relative (related person); Resistance; Risk; Role; Serum; Signal Transduction; Skeletal Muscle; Testing; Time; Tissues; Transition Elements; Venous blood sampling; Work; Yeasts; adenylate kinase; adiponectin; base; cell injury; cell type; cytokine; diabetes risk; fatty acid oxidation; glucose production; glucose tolerance; glucose uptake; hepcidin; hormone metabolism; human tissue; impaired glucose tolerance; improved; insulin secretion; insulin sensitivity; iron metabolism; lipid metabolism; macrophage; metal transporting protein 1; mitochondrial dysfunction; mouse model; muscle metabolism; novel; oxidant stress; oxidation; preference; prevent; programs; public health relevance; research study; response; stem; uptake

DESCRIPTION (provided by applicant): Iron overload, mitochondrial dysfunction and oxidative stress play pathogenic roles in the diabetes of hereditary hemochromatosis (HH) and may also be factors in common type 2 diabetes. The mouse model of HH (Hfe-/-) is characterized by decreased insulin secretion associated with oxidative stress and mitochondrial dysfunction in beta cells, although glucose tolerance is supranormal. Our studies of humans with HH reveal a similar phenotype: 31% had impaired glucose tolerance characterized by low insulin secretory capacity and increased insulin sensitivity. 22% of individuals with HH had diabetes, 89% of whom were overweight or obese suggesting that obesity-induced insulin resistance, independent of HH, could not be compensated because of the beta cell defect. Our Preliminary Data demonstrate: (A) Improved glucose tolerance in the Hfe-/- mice results from increased glucose uptake in muscle mediated by activation of AMP-dependent kinase (AMPK) and increased adiponectin, without a change in overall adiposity; (B) Decreased glucose and increased fatty acid oxidation are seen, with increased lactate production and hepatic glucose production from lactate, contributing to resistance to diet-induced obesity; (D) Mitochondria from Hfe-/- mice have increased oxidant stress resulting from a novel mechanism of iron interference with mitochondrial uptake of other metals, particularly Mn; (E) Near complete protection from obesity-associated diabetes in mice on a low iron diet; (F) Tissue iron stores are the best predictor of levels of the adipocyte hormone adiponectin in humans. All of these data are consistent with the hypothesis that iron levels, particularly as sensed by the adipocyte and skeletal muscle, lead to a phenotype protective from diabetes and obesity. At the same time, excess iron leads to beta cell damage and decreased insulin secretion. These data likely explain the association of increased iron intake with risk for type 2 diabetes and the metabolic syndrome. We propose experiments in mice to test hypotheses regarding the mechanisms for the regulation of fat and muscle metabolism by iron and the mechanisms for beta cell failure in the setting of high iron. These hypotheses will then be tested for applicability in understanding the human tissue-specific responses to iron overload. PUBLIC HEALTH RELEVANCE: High levels of iron are significantly associated with several forms of diabetes, including common type 2 diabetes and diabetes associated with the relatively common (1/200) hereditary disease hemochromatosis. In addition, iron is associated with cardiovascular disease, obesity, and lipid abnormalities that often accompany diabetes. We are studying the mechanisms for diabetes and other tissue abnormalities in humans with hereditary hemochromatosis and in a mouse model. Our data suggest that iron acts as a "poison" for mitochondria (the energy factories for cells) but also as a regulator of fat metabolism.

描述（由申请人提供）：铁过载、线粒体功能障碍和氧化应激在遗传性血色病（HH）的糖尿病中起致病作用，也可能是常见的2型糖尿病的因素。HH（Hfe-/-）小鼠模型的特征在于与β细胞中的氧化应激和线粒体功能障碍相关的胰岛素分泌减少，尽管葡萄糖耐量是超正常的。我们对HH患者的研究揭示了一个相似的表型：31%的人具有葡萄糖耐量受损，其特征是胰岛素分泌能力低和胰岛素敏感性增加。22%的HH患者患有糖尿病，其中89%的人超重或肥胖，这表明肥胖诱导的胰岛素抵抗（独立于HH）无法因β细胞缺陷而得到补偿。我们的初步数据表明：（A）Hfe-/-小鼠中改善的葡萄糖耐量是由AMP依赖性激酶（AMPK）的活化介导的肌肉中葡萄糖摄取增加和脂联素增加引起的，而总体肥胖没有改变; (B)观察到葡萄糖减少和脂肪酸氧化增加，乳酸产生增加和乳酸产生的肝葡萄糖增加，有助于抵抗饮食诱导的肥胖; (D)来自Hfe-/-小鼠的线粒体具有增加的氧化应激，这是由于铁干扰线粒体对其他金属（特别是Mn）的摄取的新机制;（E）在低铁饮食的小鼠中几乎完全保护免于肥胖相关的糖尿病;（F）组织铁储存是人类脂肪细胞激素脂联素水平的最佳预测因子。所有这些数据都与铁水平，特别是脂肪细胞和骨骼肌所感知的铁水平，导致防止糖尿病和肥胖的表型的假设一致。同时，过量的铁会导致β细胞损伤和胰岛素分泌减少。这些数据可能解释了铁摄入量增加与2型糖尿病和代谢综合征风险之间的关系。我们提出在小鼠身上进行实验，以测试有关铁调节脂肪和肌肉代谢的机制以及高铁环境下β细胞衰竭机制的假设。然后，这些假设将被测试的适用性，在了解人体组织特异性的反应，铁过载。公共卫生关系：高水平的铁与几种形式的糖尿病显著相关，包括常见的2型糖尿病和与相对常见的（1/200）遗传性疾病血色素沉着症相关的糖尿病。此外，铁还与心血管疾病、肥胖和血脂异常有关，这些疾病通常伴随糖尿病。我们正在研究遗传性血色病患者和小鼠模型中糖尿病和其他组织异常的机制。我们的数据表明，铁是线粒体（细胞的能量工厂）的“毒药”，但也是脂肪代谢的调节剂。