Mechanisms of Dietary Lipid Induced Insulin Resistance

越来越多的证据表明，肥胖和相关疾病，如胰岛素抵抗和糖尿病，在全球范围内流行。在过去的几十年里，这些情况迅速上升的一个主要原因与典型饮食中卡路里负荷和高脂肪含量的增加有关。因此，了解过量饮食和特定的常量营养素(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人口的所有部分都至关重要。我们最近证明，大量富含饱和脂肪酸(SFA)的饮食具有独特的能力，可以在人体内诱导快速(24小时内)和严重的全身胰岛素抵抗(葡萄糖利用率下降约50%)。重要的是，在饲喂富含SFA的饲料期间，组织中的初始生化和信号通路特征表明，这些变化与胰岛素抵抗或糖尿病的慢性状态下通常存在的变化一致。当前建议的第一个目标(目标1)是利用这一新的和生理上相关的东西，它得到了基于实验室的研究和初步临床数据的支持。 模型，以确定细胞和组织中导致饮食饱和脂肪诱导的胰岛素抵抗的关键信号通路/机制。研究的主要机制或“途径”将包括生物活性脂质中间体的形成，内质网应激的产生，以及诱导单核细胞、骨骼肌和脂肪组织以及组织和全身炎症的线粒体功能障碍/活性氧物种。这种人类胰岛素抵抗模型的快速特性将极大地促进识别胰岛素抵抗代谢变化的早期和更近的机制。目标1将通过两项临床研究来实现，以确定富含饱和脂肪的饮食挑战与“健康”饮食挑战对全身胰岛素敏感性的影响以及上述机制途径。在糖代谢正常和异常的人群中，测定和比较高SFA饮食的效果，也将有助于深入了解基线糖耐量/胰岛素抵抗对膳食脂肪挑战反应的程度和机制的影响。目的2将在一项交叉研究中确定饮食组成(单不饱和脂肪与碳水化合物)对饮食诱导胰岛素抵抗途径的影响。在目标3中，参与者将在高SFA摄入量的增加阶段进行研究，比较急性(1餐)、亚急性(SFA饮食的一个24小时周期)和更慢性的时间框架(4个SFA饮食周期)的组织成分和途径的变化。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，获得对途径事件的时间序列的洞察，识别起始和继发途径的变化，并澄清组织之间潜在的串扰。这些研究的一个主要目标将是证明该模型可以作为一种有价值的临床研究工具来研究饮食诱导人类胰岛素抵抗的潜在机制。由于这是一个快速和生理学的胰岛素抵抗模型，它提供了快速加快研究饮食脂肪(以及潜在的其他常量营养素)对胰岛素抵抗的影响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.