13C MRS Studies of Brain Mitochondrial Metabolism in Insulin Resistance

描述(申请人提供)：胰岛素抵抗已被发现是阿尔茨海默病和其他与年龄相关的神经疾病发展的强烈风险因素。我们已经证明，肌肉线粒体氧化代谢降低在衰老、糖尿病前期和糖尿病的胰岛素抵抗的病因中起着关键作用。然而，目前还不知道大脑中是否有类似的下降。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。在这项建议中，我们将测试线粒体代谢减少是否是胰岛素抵抗中与年龄相关的神经疾病的危险因素。我们将结合13C MRS来测量神经元TCA周期的速率，并结合31P MRS来测量能量应激。13C MRS具有测量神经元和神经胶质细胞TCA周期的独特能力--这是对体内线粒体氧化能量产生的直接测量。我们和其他人使用MRS表明，80%的神经元线粒体能量产生支持神经元信号传递，这意味着即使线粒体能力的微小损伤也可能损害大脑功能。最近我们将这些方法应用于健康老年受试者的研究。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、胰岛素抵抗的受试者神经元线粒体支持大脑功能的能量需求的能力降低，这可能使他们容易患上与年龄相关的神经疾病。我们将在其他健康的非肥胖、胰岛素抵抗的受试者身上测试我们的假设，这些受试者的父母中至少有一人患有2型糖尿病。在我们的代谢研究中，我们广泛地对这些受试者进行了大量的表型分析，因为他们允许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对健康的影响。

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.