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: 8117185
• 负责人: DONALD A. MCCLAIN
• 金额: $ 41.43万
• 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/8117185
• 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; Health; 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

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）：铁超载、线粒体功能障碍和氧化应激在遗传性血色素沉着症（HH）糖尿病中起致病作用，也可能是常见2型糖尿病的因素。小鼠HH （Hfe-/-）模型的特征是β细胞中与氧化应激和线粒体功能障碍相关的胰岛素分泌减少，尽管糖耐量异常。我们对HH患者的研究揭示了类似的表型：31%的患者糖耐量受损，表现为胰岛素分泌能力低下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，这表明肥胖引起的胰岛素抵抗，独立于HH，由于β细胞缺陷不能得到补偿。我们的初步数据表明：(A) Hfe-/-小鼠的葡萄糖耐量改善是由于amp依赖性激酶（AMPK）激活介导的肌肉葡萄糖摄取增加和脂联素增加，而总体肥胖没有变化；