Decreased Fat Oxidation - Metabolic Inflexibility in African-American Women

描述(由申请人提供)：导致肥胖和2型糖尿病(T2 DM)的种族差异的机制，与高加索女性相比，在非裔美国人(AA)女性中尤为明显，目前尚不清楚。虽然社会经济地位和饮食习惯等因素可能起到一定作用，但新出现的数据表明，底物利用的差异可能会导致这些差异。有证据表明，在隔夜禁食、锻炼或高脂肪喂养期间，AA女性的新陈代谢缺乏灵活性，而且不会增加脂肪氧化到高加索女性观察到的水平。低脂肪氧化可导致脂肪重新定向到脂肪组织中储存，并增加甘油三酯和脂肪毒性代谢物在骨骼肌中的储存，导致胰岛素抵抗(IR)和糖尿病风险增加。在AA女性中观察到更大的胰岛素抵抗。与高加索女性相比，再生障碍性贫血患者的这些观察结果与肥胖胰岛素抵抗患者的代谢不灵活现象相似。虽然AA女性表现为IR，但她们的内脏和肝脏脂肪堆积水平较低。这是一个矛盾的发现，因为内脏和肝脏的脂肪储存是IR和代谢性疾病的强烈风险因素。综上所述，这些数据表明，与高加索女性相比，再生障碍性贫血患者的胰岛素抵抗表型是不同的，胰岛素敏感性较低可能是由于骨骼肌的差异，导致外周胰岛素抵抗。然而，我们没有发现比较肝脏和外周胰岛素敏感性的报告，而且AA女性的骨骼肌特征数据也非常有限，这些特征已被证明与肥胖和T2 DM患者的胰岛素抵抗有关。有限的数据支持AA女性骨骼肌中肌肉脂肪堆积增加和胰岛素抵抗的作用，但我们没有发现关于AA女性脂肪毒性脂质水平或线粒体含量的数据。基于这些观察，我们的假设是，AA女性骨骼肌固有的差异会导致骨骼肌中脂肪氧化和脂质代谢产物的积累受损，并与AA女性肥胖、胰岛素抵抗和2型糖尿病的发展有关。为了应对这一假设，我们制定了3个目标：1)确定再生障碍性贫血和高加索女性在次最大运动量运动时的脂肪氧化；2)确定已证明与胰岛素敏感性有关的脂肪堆积和骨骼肌特征(如肌肉纤维类型、毛细血管密度、氧化能力、线粒体含量)；以及3)评估胰岛素敏感性(外周和肝脏)，并研究胰岛素敏感性、脂肪氧化和骨骼肌特征之间的关系。在我们开始梳理在脂肪氧化和胰岛素敏感性的种族差异中起作用的环境和遗传因素之前，我们需要更好地了解潜在的生理学。我们建议使用最先进的技术进行的详细的体内和体外评估将提供详细的表型信息，这将为观察到再生障碍性贫血女性II型糖尿病患病率的增加提供有价值的洞察。 与公共卫生相关：非裔美国女性患肥胖症或糖尿病的可能性是高加索女性的两倍。这些健康差异的原因尚不清楚，但越来越多的证据表明，AA女性脂肪氧化程度较低会导致骨骼肌内脂肪积累，这可能导致胰岛素抵抗和糖尿病的发展。在我们开始了解在肥胖和糖尿病的种族差异中起作用的环境和遗传因素之前，我们需要更好地了解与脂肪氧化相关的代谢和骨骼肌特征，这可能会导致AA女性发生代谢性疾病的风险增加。

DESCRIPTION (provided by applicant): Mechanisms responsible for the racial disparity in obesity and Type 2 diabetes (T2DM) that are particularly apparent in African-American (AA) women compared to Caucasian women are not understood. While factors such as socioeconomic status and dietary habits likely play a role, emerging data suggests that differences in substrate utilization may contribute to these disparities. Evidence suggests that AA women are metabolically inflexible after an overnight fast, during exercise, or during high fat feeding, and do not increase fat oxidation to levels observed in Caucasian women. Low fat oxidation could result in redirection of lipid into adipose tissue for storage, as well as increased storage of triglyceride and lipotoxic metabolites within skeletal muscle, leading to insulin resistance (IR) and increased risk for development of diabetes. Greater insulin resistance is observed in AA women. These observations in AA compared to Caucasian women are similar to the metabolic inflexibility observed in obese insulin resistant compared to lean individuals. While AA women demonstrate IR, they have lower levels of visceral and hepatic lipid accumulation. This is a paradoxical finding as visceral and hepatic lipid stores are strong risk factors for IR and metabolic diseases. Taken together, the data suggests that IR is phenotypically distinct in AA compared to Caucasian women, and that the lower insulin sensitivity may be due differences in skeletal muscle, leading to peripheral IR. However, we could find no reports comparing hepatic and peripheral insulin sensitivity, and very limited data in AA women for skeletal muscle characteristics that have been demonstrated to be related to insulin resistance in obese and T2DM subjects. Limited data supports a role for increased muscle lipid accumulation in skeletal muscle and insulin resistance in AA women, but we could find no data on lipotoxic lipid levels or mitochondrial content in AA women. Based on these observations, our hypothesis is that inherent differences in skeletal muscle in AA women results in impaired fat oxidation and accumulation of lipid and lipid metabolites within skeletal muscle, and is a link between the development of obesity, insulin resistance and Type 2 diabetes in AA women. To address this hypothesis we have developed 3 Aims: 1) Determine fat oxidation during sub-maximal exercise in AA and Caucasian women; 2) Determine lipid accumulation and skeletal muscle characteristics (e.g. muscle fiber type, capillary density, oxidative capacity, mitochondrial content) that have been shown to be related to insulin sensitivity; and 3) Assess insulin sensitivity (peripheral and hepatic), and examine the relationship between insulin sensitivity, fat oxidation and skeletal muscle characteristics. Before we can begin to tease apart environmental and genetic factors that play a role in racial differences in fat oxidation and insulin sensitivity, we need to gain a better understanding of the underlying physiology. The detailed in vivo and ex vivo evaluations we propose using state of the art techniques will provide detailed phenotype information that will provide valuable insight into the increased prevalence of Type II diabetes observed in AA women. PUBLIC HEALTH RELEVANCE: The likelihood of being obese or having diabetes is twice as high in African-American women compared to Caucasian women. Reasons for these health disparities are not understood, but growing evidence suggests that lower fat oxidation in AA women leads to accumulation of fat within skeletal muscle which can lead to the development of insulin resistance and diabetes. Before we can begin to understand the environmental and genetic factors that play a role in racial differences in obesity and diabetes, we need to gain a better understanding of the metabolism and skeletal muscle characteristics related to fat oxidation which may lead to the increased risk of development of metabolic diseases in AA women.