13C MRS Studies of Brain Mitochondrial Metabolism in Insulin Resistance

描述（由申请人提供）：已发现胰岛素抵抗是阿尔茨海默病和其他年龄相关神经系统疾病发展的一个强有力的风险因素。我们已经表明，减少肌肉线粒体氧化代谢在衰老、糖尿病前期和糖尿病中的胰岛素抵抗的病因学中起关键作用。但是，目前还不清楚大脑中是否存在类似的减少。线粒体功能障碍与衰老、阿尔茨海默病和其他神经退行性疾病的认知能力下降有关。在这个提议中，我们将测试线粒体代谢降低是否是胰岛素抵抗中与年龄相关的神经系统疾病的危险因素。我们将结合联合收割机13 C MRS测量神经元TCA周期的速率和31 P MRS测量能量应激。13 C MRS具有测量神经元和神经胶质TCA循环速率的独特能力-直接测量体内线粒体氧化能产生。我们和其他人已经使用MRS表明，80%的神经元线粒体能量产生支持神经元信号传导，这意味着即使是线粒体能力的微小损伤也可能损害脑功能。最近，我们将这些方法应用于研究健康的老年受试者。我们发现枕叶的能量代谢发生了深刻的变化，包括神经元TCA周期减少了28%。我们的一般假设是，健康的非糖尿病、胰岛素抵抗受试者的神经元线粒体支持脑功能能量需求的能力降低，这可能使他们易患与年龄相关的神经系统疾病。我们将在其他健康的非肥胖、胰岛素抵抗的受试者中检验我们的假设，这些受试者是至少一个患有2型糖尿病的父母的后代。在我们的代谢研究中，我们对这些受试者进行了广泛的表型分析，因为他们可以独立于糖尿病和肥胖症的并发症来研究慢性胰岛素抵抗的病因和健康影响。

DESCRIPTION (provided by applicant): Insulin resistance has been found to be a strong risk factor in the development of Alzheimer's disease and other age related neurological disorders. We have shown that reduced muscle mitochondrial oxidative metabolism plays a key role in the etiology of insulin resistance in aging, pre-diabetes, and diabetes. However it is not known whether there is a similar decrease in the brain. Mitochondrial dysfunction has been implicated in the cognitive decline with aging, Alzheimer's disease and other neurodegenerative disorders. In this proposal we will test whether reduced mitochondrial metabolism is a risk factor for age related neurological disorders in insulin resistance. We will combine 13C MRS to measure the rate of the neuronal TCA cycle with 31P MRS to measure energetic stress. 13C MRS has the unique capability to measure the rates of the neuronal and glial TCA cycles - a direct measure of in vivo mitochondrial oxidative energy production. We and others have used MRS to show that 80% of neuronal mitochondrial energy production supports neuronal signaling, with the implication that even small impairments in mitochondrial capacity could compromise brain function. Recently we applied these methods to study healthy elderly subjects. We found profound alterations in energy metabolism in the occipital lobe, including a 28% reduction in the neuronal TCA cycle. Our general hypothesis is that healthy non-diabetic, insulin-resistant subjects have a reduced capacity of neuronal mitochondria to support energetic requirements of brain function which may predispose them to age-related neurological disorders. We will test our hypothesis in otherwise healthy non-obese, insulin-resistant subjects who are the offspring of at least one parent with type 2 diabetes. In our metabolic studies we have extensively phenotyped a large cohort of these subjects because they allow the etiology and health impacts of chronic insulin resistance to be studied independent of the complications of diabetes and obesity.