Mechanisms of Dietary Lipid Induced Insulin Resistance

膳食脂质诱导胰岛素抵抗的机制

• 批准号: 8458880
• 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/8458880
• 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; 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，肥胖症以及胰岛素抵抗和糖尿病等相关疾病在世界范围内流行。在过去的几十年里，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的增加和高脂肪含量有关。因此，了解饮食过量和特定常量营养素（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，可以诱导人类快速（在24小时内）和深刻的全身胰岛素抵抗（约50%的葡萄糖利用率下降）。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慢性状态下的典型变化一致。目前提议的第一个目标（目标1）是利用这种新颖的生理相关的优势，这一目标得到了实验室研究和初步临床数据的支持