IRON AND METABOLISM: ALTERED FUEL OXIDATION AND MITOCHONDRIAL DYSFUNCTION

描述(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沉着症(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-/-)小鼠模型的特征是胰岛素分泌减少，伴随着氧化应激和β细胞线粒体功能障碍，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%的人糖耐量受损，特征是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-/-小鼠葡萄糖耐量的改善是由于AMP依赖的激酶(AMPK)的激活和脂联素的增加而导致肌肉中葡萄糖摄取的增加，而总体肥胖度没有变化； (B)葡萄糖减少，脂肪酸氧化增加，乳酸产生增加，肝脏从乳酸产生葡萄糖，有助于抵抗饮食引起的肥胖； (D)由于铁干扰线粒体吸收其他金属，尤其是锰，从而使HFe-/-小鼠的线粒体氧化应激增加；(E)低铁饮食小鼠几乎完全预防肥胖相关的糖尿病；(F)组织铁储存是人类脂肪细胞荷尔蒙脂联素水平的最佳预测指标。所有这些数据都符合这样的假设，即铁的水平，特别是脂肪细胞和骨骼肌检测到的铁水平，会导致一种防止糖尿病和肥胖症的表型。与此同时，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联。我们建议在小鼠身上进行实验，以测试关于铁调节脂肪和肌肉代谢的机制以及高铁环境下β细胞衰竭的机制的假说。然后将测试这些假说在理解人类对铁超载的组织特异性反应方面的适用性。公共卫生相关性：高铁水平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遗传性疾病血色素沉着症(1/200)相关的糖尿病。此外，铁还与经常伴随糖尿病的心血管疾病、肥胖症和血脂异常有关。我们正在研究人类遗传性血色素沉着症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，铁不仅是线粒体(细胞的能量工厂)的“毒药”，也是脂肪新陈代谢的调节剂。

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.