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: 8307910
• 负责人: DONALD A. MCCLAIN
• 金额: $ 41.29万
• 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/8307910
• 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; 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; research study; response; stem; uptake

Program Director/Principal Investigator (Last, First, Middle): McClain, Donald A 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. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

项目主任/主要研究者（最后，第一，中间）：麦克莱恩，唐纳德A 铁超载、线粒体功能障碍和氧化应激在糖尿病中起致病作用， 遗传性血色素沉着症（HH），也可能是常见的2型糖尿病的因素。的小鼠模型 HH（Hfe-/-）的特征在于与氧化应激和线粒体损伤相关的胰岛素分泌减少。 β细胞功能障碍，尽管葡萄糖耐量是超正常的。我们对人类HH的研究揭示了 相似的表型：31%的人葡萄糖耐量受损，其特征是胰岛素分泌能力低下， 增加胰岛素敏感性。22%的HH患者患有糖尿病，其中89%超重或肥胖 这表明，肥胖诱导的胰岛素抵抗，独立于HH，不能得到补偿，因为 β细胞缺陷我们的初步数据表明：（A）Hfe-/-小鼠中改善的葡萄糖耐量 由AMP依赖性激酶（AMPK）激活介导的肌肉中葡萄糖摄取增加引起， 脂联素增加，总体肥胖没有变化;（B）葡萄糖减少，脂肪酸增加 观察到氧化，乳酸产生增加，乳酸产生的肝葡萄糖增加， （D）来自Hfe-/-小鼠的线粒体具有增加的氧化应激，导致 铁干扰线粒体摄取其他金属，特别是Mn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 这是人类脂肪细胞激素脂联素水平的最佳预测指标。所有这些数据都是一致的 假设铁水平，特别是脂肪细胞和骨骼肌所感受到的铁水平， 表型保护免受糖尿病和肥胖症。同时，过量的铁会导致β细胞损伤， 胰岛素分泌减少。这些数据很可能解释了铁摄入量增加与型糖尿病风险之间的关系。 2型糖尿病与代谢综合征。我们建议在小鼠中进行实验，以检验关于 铁对脂肪和肌肉代谢的调节机制以及 高铁的设置。然后，这些假设将被测试，以了解人类的适用性。 对铁过载的组织特异性反应 PHS 398/2590（Rev. 11/07）