In vivo and in vitro studies of dietary fatty acids eNOS polymorphisms and insulin resistance in the endothelium

膳食脂肪酸 eNOS 多态性和内皮胰岛素抵抗的体内和体外研究

• 批准号: BB/E021816/1
• 负责人: Christine Williams
• 金额: $ 44.64万
• 依托单位: University of Reading
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE021816%2F1
• 关键词: vivo; vitro; studies; dietary; fatty

The hormone insulin is involved in stimulating the uptake and metabolism of dietary carbohydrates (e.g. sugars) and fats by cells such as those in muscle, fat tissue and liver. When insufficient insulin is produced (type 1 diabetes), or when there is lack of effect of insulin on cells (type 2 diabetes and insulin resistance), the metabolism of carbohydrates and fats becomes abnormal. Levels of blood glucose rise, leading to symptoms of diabetes (thirst, tiredness etc) and blood lipids also rise. Lipids are carried in the blood on complex particles called lipoproteins (e.g. LDL and HDL cholesterol). In diabetes these particles are abnormal, with low HDL cholesterol (good cholesterol) and raised concentrations of particles called triglyceride rich lipoproteins. This combination is known to increase the risk of cholesterol penetrating the blood vessel wall, leading to hardening of the arteries and heart disease. For a long time it was thought that the reason people with diabetes have a much higher risk of heart disease was because of these abnormal lipoprotein particles. Whilst this is undoubtedly part of the story, new research is suggesting other mechanisms may also be involved. Although we have known for a long time that cells such as muscle, fat and liver require insulin, it is only recently that insulin has been shown to be required for the normal healthy functioning of the cells that line the blood vessel wall (called endothelial cells). Insulin increases the formation of compounds which keep the blood vessel wall dilated and reduces release of compounds which constrict the blood vessel wall and cause it to become sticky (called inflammatory proteins). This new research is helping to understand how insulin triggers the release of compounds which keep the vessel wall healthy and what happens when people become resistant to the normal actions of insulin. People who are diabetic or insulin resistant are unable to dilate their blood vessels normally when stimulated and release inflammatory proteins which are more likely to lead to cholesterol depositing in the artery wall. The reason there is increasing concern about insulin resistance is that this condition is becoming extremely common because it is linked with overweight and obesity. It is now estimated that as many as 20% of middle aged adults may be insulin resistant and this greatly increases their risk of getting heart disease or having a stroke. Understanding the consequences of insulin resistance in blood vessel cells is therefore very important. Some research has shown that the types of fats in the diet can influence the efficiency with which insulin acts on muscle, fat and liver cells. However very little is known about how the type of dietary fat influences endothelial cells and how the cells behave when exposed to different fats, both in the body and when studied in test tubes. We will use a technique to study the behavior of blood vessels in people when they are exposed to high concentrations of different types of fats and also how it affects their blood vessel response when insulin is given. We will also study cells cultured in the laboratory to see if we can understand the triggers that lead to the cells responding more or less favourably in the presence of different types of fats. One of the compounds which help the blood vessel wall to dilate is a small molecule called nitric oxide. The enzyme which leads to the release of nitric oxide is a protein whose structure varies slightly in some people due to differences in their genes (about 12% the population carry this variation and are known to be more at risk of heart disease). We want to study people with and without this variation and see if they respond differently to different fats. We will also study blood vessel cells (from the umbilical cord) which have been obtained from women with and without the variant to see how this enzyme works.

激素胰岛素参与刺激诸如肌肉、脂肪组织和肝脏中的细胞对膳食碳水化合物（例如糖）和脂肪的摄取和代谢。当胰岛素产生不足时（1型糖尿病），或者当胰岛素对细胞缺乏作用时（2型糖尿病和胰岛素抵抗），碳水化合物和脂肪的代谢变得异常。血糖水平上升，导致糖尿病症状（口渴，疲劳等）和血脂也上升。脂质在血液中通过称为脂蛋白的复杂颗粒（例如LDL和HDL胆固醇）携带。在糖尿病中，这些颗粒是异常的，具有低HDL胆固醇（好胆固醇）和称为富含甘油三酯的脂蛋白的颗粒浓度升高。已知这种组合会增加胆固醇穿透血管壁的风险，导致动脉硬化和心脏病。长期以来，人们认为糖尿病患者患心脏病的风险更高的原因是因为这些异常的脂蛋白颗粒。虽然这无疑是故事的一部分，但新的研究表明，其他机制也可能参与其中。虽然我们很久以前就知道肌肉、脂肪和肝脏等细胞需要胰岛素，但直到最近才发现胰岛素是血管壁细胞（称为内皮细胞）正常健康功能所必需的。胰岛素增加了保持血管壁扩张的化合物的形成，并减少了收缩血管壁并使其变得粘稠的化合物（称为炎症蛋白）的释放。这项新的研究有助于了解胰岛素如何触发保持血管壁健康的化合物的释放，以及当人们对胰岛素的正常作用产生抵抗时会发生什么。糖尿病或胰岛素抵抗的人在受到刺激时无法正常扩张血管，并释放炎症蛋白，这些蛋白更有可能导致胆固醇沉积在动脉壁上。人们越来越关注胰岛素抵抗的原因是，这种情况变得非常普遍，因为它与超重和肥胖有关。据估计，多达20%的中年人可能患有胰岛素抵抗，这大大增加了他们患心脏病或中风的风险。因此，了解血管细胞中胰岛素抵抗的后果非常重要。一些研究表明，饮食中的脂肪类型会影响胰岛素作用于肌肉、脂肪和肝细胞的效率。然而，人们对膳食脂肪的类型如何影响内皮细胞以及细胞在体内和试管中研究时暴露于不同脂肪时的行为知之甚少。我们将使用一种技术来研究当人们暴露于高浓度的不同类型的脂肪时血管的行为，以及当给予胰岛素时它如何影响他们的血管反应。我们还将研究在实验室中培养的细胞，看看我们是否能理解导致细胞在不同类型的脂肪存在下或多或少做出有利反应的触发因素。其中一种帮助血管壁扩张的化合物是一种叫做一氧化氮的小分子。导致一氧化氮释放的酶是一种蛋白质，由于基因的差异，其结构在某些人中略有不同（约12%的人口携带这种变异，并且已知更容易患心脏病）。我们想研究有这种变异和没有这种变异的人，看看他们对不同脂肪的反应是否不同。我们还将研究从有和没有变异的妇女身上获得的血管细胞（来自脐带），以了解这种酶如何工作。

项目成果

Effect of the endothelial nitric oxide synthase Glu298Asp polymorphism on endothelial function and lipid profile in healthy subjects

内皮一氧化氮合酶 Glu298Asp 多态性对健康受试者内皮功能和血脂的影响

• 发表时间: 2011
• 作者: AK Thompson

Abstract: P459 IMPACT OF ELEVATED FREE FATTY ACIDS ON INSULIN AND MARKERS OF INFLAMMATION AND ENDOTHELIAL FUNCTION

摘要：P459 游离脂肪酸升高对胰岛素以及炎症和内皮功能标志物的影响

• DOI: 10.1016/s1567-5688(09)70754-8
• 发表时间: 2009
• 期刊: Atherosclerosis Supplements
• 作者: Newens K

Acute effects of elevated NEFA on vascular function: a comparison of SFA and MUFA.

• DOI: 10.1017/s0007114510004976
• 发表时间: 2011-05
• 期刊: The British journal of nutrition
• 作者: K. Newens;A. Thompson;K. Jackson;John W. Wright;Christine M. Williams

Insulin sensitivity during acute elevation of non-esterified fatty acids: Influence of fat composition and gender.

非酯化脂肪酸急性升高期间的胰岛素敏感性：脂肪成分和性别的影响。

• 发表时间: 2010
• 作者: KJ Newens

P333 Dietary fatty acids influence endothelial function during acute NEFA elevation.

P333 膳食脂肪酸在 NEFA 急性升高期间影响内皮功能。

• 发表时间: 2010
• 作者: A Thompson