Mechanisms of Dietary Lipid Induced Insulin Resistance

膳食脂质诱导胰岛素抵抗的机制

• 批准号: 8793742
• 负责人: Peter D Reaven
• 金额: --
• 依托单位: PHOENIX VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793742
• 关键词: Accounting; Acute; Adipose tissue; Animal Model; Animals; Biochemical Pathway; Blindness; Bypass; Carbohydrates; Cardiovascular Diseases; Cells; Chronic; Clinical Data; Clinical Research; Critical Pathways; Cross-Over Studies; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Dietary Fatty Acid; Early identification; Employee Strikes; Epidemic; Event; Fatty Liver; Fatty acid glycerol esters; Foundations; General Population; Generations; Glucose; Glucose Intolerance; Goals; Health; Hour; Human; Human Characteristics; Hyperphagia; Hypertension; In Vitro; Individual; Inflammation; Inflammatory; Infusion procedures; Insulin; Insulin Resistance; Insulin Resistance Pathway; Intake; Intervention; Intravenous; Kidney Failure; Laboratories; Lead; Life Style; Link; Lipids; Macronutrients Nutrition; Malignant Neoplasms; Mediating; Medical; Metabolic; Metabolism; Modeling; Monounsaturated Fatty Acids; Muscle; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Overweight; Oxygen; Participant; Pathway interactions; Peripheral; Physiological; Plasma; Polycystic Ovary Syndrome; Population; Process; Property; Protocols documentation; Reactive Oxygen Species; Risk; Role; Saturated Fatty Acids; Signal Pathway; Signal Transduction; Skeletal Muscle; Stroke; Testing; Time; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Unsaturated Fatty Acids; Veterans; Weight Gain; base; cell type; cost; dietary excess; endoplasmic reticulum stress; feeding; glucose metabolism; glucose tolerance; good diet; insight; insulin sensitivity; insulin signaling; intravenous administration; liver metabolism; mitochondrial dysfunction; monocyte; monounsaturated fat; novel; physiologic model; resistance mechanism; response; saturated fat; targeted treatment; tool

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.

越来越多的证据表明，肥胖症和相关疾病（例如胰岛素抵抗和糖尿病）的流行病。在过去的几十年中，这些条件下快速上升的主要原因与热量量的增加以及典型饮食的高脂肪含量有关。因此，了解饮食过多和特定的大量营养素（例如饱和脂肪）对胰岛素抵抗的发展以及实现这一目标的潜在机制的贡献至关重要。我们最近证明，在饱和脂肪酸（SFA）中极大地富集的饮食具有独特的能力，可以诱导人类迅速（在24小时）和全身胰岛素耐药性（葡萄糖利用率下降约50％）的速度（在D 24小时内）。重要的是，在富含SFA的饮食过程中，组织中最初的生化和信号途径表征在组织中表征，表明与通常存在于胰岛素抵抗或糖尿病的慢性状态的变化一致。由实验室研究和初步临床数据支持的当前建议的第一个目标（AIM 1）将是利用这一小说和生理上相关的 模型以识别负责饮食饱和脂肪诱导胰岛素抵抗的细胞和组织中的关键信号途径/机制。所检查的主要机制或“途径”将包括形成生物活性脂质中间体，产生ER应激以及单核细胞中线粒体功能障碍/反应性氧的诱导，骨骼肌和脂肪组织组织以及组织和组织炎症。这种人类胰岛素抵抗模型的快速性质将极大地促进胰岛素抵抗代谢变化的早期和更近端机制。 AIM 1将通过进行两项临床研究来确定饱和脂肪富集的影响与“健康”饮食挑战对全身胰岛素敏感性以及上述注明的机制途径的影响。确定和比较富含SFA的饮食在正常和异常葡萄糖代谢的饮食中的影响，还将洞悉基线葡萄糖耐受性/胰岛素耐药性对饮食脂肪挑战的反应程度和机制的影响。 AIM 2将在交叉研究中确定饮食成分（单不饱和脂肪与碳水化合物）对饮食诱导胰岛素抵抗的途径的影响。在AIM 3中，将在不断增加的SFA摄入量增加的时间内研究参与者，从而比较急性（1粉），亚急性（SFA饮食的24小时周期）和更多慢性时帧（4个SFA饮食周期）的组织成分和途径的变化。该目标将有助于确定反复饮食挑战对胰岛素抵抗的影响，对途径事件的时间序列的见解，识别启动和次要途径的变化，并阐明组织之间的潜在跨语言。这些研究的主要目的是证明该模型可以成为研究人类饮食诱导的胰岛素抵抗的基本机制的宝贵临床研究工具。由于这是一种胰岛素抵抗的快速而生理的模型，因此它提供了快速加速对饮食脂肪（以及潜在的其他大型营养素）对胰岛素抵抗和潜在疗法的影响和机制的调查速度的能力，以阻止这些过程。