Mechanisms of Dietary Lipid Induced Insulin Resistance

越来越多的证据表明，肥胖症和相关疾病如胰岛素抵抗和糖尿病在世界范围内流行。在过去几十年中，这些疾病迅速增加的一个主要原因与典型饮食中热量负荷和高脂肪含量的增加有关。因此，了解饮食过量和特定宏量营养素（如饱和脂肪）对胰岛素抵抗发展的贡献以及实现这一目标的潜在机制对我们所有人群都至关重要。我们最近证明，富含饱和脂肪酸（SFA）的饮食具有独特的能力，可诱导人体快速（24小时内）和深刻的全身胰岛素抵抗（葡萄糖利用率下降约50%）。重要的是，在饲喂富含SFA的饮食期间，组织中的初始生化和信号途径表征表明与胰岛素抵抗或糖尿病的慢性状态中通常存在的那些变化一致。当前提案的第一个目标（Aim 1）得到了实验室研究和初步临床数据的支持，将利用这种新颖且生理相关的 模型，以确定负责膳食饱和脂肪诱导的胰岛素抵抗的细胞和组织中的关键信号通路/机制。检查的主要机制或“途径”将包括生物活性脂质中间体的形成，ER应激的产生，以及单核细胞、骨骼肌和脂肪组织中线粒体功能障碍/活性氧物质的诱导，以及组织和全身炎症。这种胰岛素抵抗的人类模型的快速性质将极大地促进胰岛素抵抗的代谢变化的早期和因此更近端的机制的鉴定。目标1将通过进行两项临床研究来实现，以确定富含饱和脂肪与“健康”饮食挑战对全身胰岛素敏感性和上述机制途径的影响。确定和比较高SFA-富集饮食对正常和异常葡萄糖代谢的影响，也将提供对基线葡萄糖耐量/胰岛素抵抗对膳食脂肪挑战反应程度和机制的影响的深入了解。目标2将在交叉研究中确定膳食组成（单不饱和脂肪与碳水化合物）对胰岛素抵抗膳食诱导途径的影响。在目标3中，将在增加高SFA摄入量的时间段内对参与者进行研究，比较急性（1餐）、亚急性（一个24小时周期的SFA饮食）和更慢性的时间范围（4个周期的SFA饮食）的组织组成和途径变化。这一目标将有助于确定反复饮食挑战对胰岛素抵抗的影响，深入了解途径事件的时间顺序，识别起始和次级途径变化，并澄清组织之间的潜在串扰。这些研究的一个主要目标将是证明该模型可以是一个有价值的临床研究工具，以研究饮食诱导的人类胰岛素抵抗的机制。由于这是胰岛素抵抗的快速和生理模型，因此它提供了快速加速研究膳食脂肪（以及潜在的其他大量营养素）对胰岛素抵抗的作用和机制以及阻止这些过程的潜在疗法的能力。

There is increasing evidence of a worldwide epidemic of obesity and related conditions such as insulin resistance and diabetes. A major reason for the rapid rise in these conditions over the past several decades is related to increases in the caloric load and high fat content of typical diets. Understanding the contributions of dietary excess and specific macronutrients such as saturated fat to the development of insulin resistance and the underlying mechanisms by which this is achieved is therefore of critical importance for all segments of our population. We have recently demonstrated that a diet greatly enriched in saturated fatty acids (SFA) has a unique ability to induce a rapid (in d 24 hours) and profound whole body insulin resistance (~ 50% decline in glucose utilization) in humans. Importantly, initial biochemical and signal pathway characterization in tissues during the feeding of SFA-enriched diets indicates changes consistent with those typically present in chronic states of insulin resistance or diabetes. The first goal (Aim 1) of the current proposal, which is supported by both laboratory based studies and preliminary clinical data, will be to take advantage of this novel and physiologically relevant model to identify key signal pathways/mechanisms in cells and tissues responsible for dietary saturated fat induced insulin resistance. Primary mechanisms or "pathways" examined will include formation of bioactive lipid intermediates, generation of ER stress, and induction of mitochondrial dysfunction/reactive oxygen species in monocytes, skeletal muscle and adipose tissue as well as tissue and systemic inflammation. The rapid nature of this human model of insulin resistance will greatly facilitate identification of the early and therefore more proximal mechanisms underlying the metabolic changes of insulin resistance. Aim 1 will be achieved by conducting two clinical studies to determine the effects of saturated fat- enriched vs. "healthy" diet challenges on whole body insulin sensitivity and on the above noted mechanism pathways. Determining and comparing the effects of high SFA-enriched diets in those with normal and abnormal glucose metabolism, will also provide insight into the effect of baseline glucose tolerance/insulin resistance on the extent and mechanisms of responses to dietary fat challenge. Aim 2 will determine in a cross-over study the effects of dietary composition (monounsaturated fats vs. carbohydrates) on pathways of dietary induction of insulin resistance. In Aim 3, participants will be studied over increasing periods of high SFA intake, providing a comparison of changes in tissue composition and pathways over acute (1 meal), subacute (one 24-hour cycle of the SFA diet) and more chronic time frames (4 cycles of SFA diets). This aim will help determine the effects of repeated diet challenges on insulin resistance, gain insights into the temporal sequence of pathway events, identify initiating and secondary pathway changes, and clarify potential cross-talk between tissues. A major goal of these studies will be to demonstrate that this model can be a valuable clinical research tool to investigate mechanism underlying dietary induced insulin resistance in humans. As this is a rapid and physiologic model of insulin resistance, it provides the ability to rapidly accelerate the pace of investigatios into both effects and mechanisms of dietary fat (and potentially other macronutrients) on insulin resistance and potential therapies to arrest these processes.