Niacin, n-3 fatty acids and insulin resistance

描述（由申请人提供）：胰岛素抵抗综合征（IRS）困扰着大约4700万美国人。其主要成分包括向心性肥胖、甘油三酯升高、高密度脂蛋白胆固醇（HDL-C）水平降低、空腹高血糖症和/或高血压。患有IRS的个体患2型糖尿病和/或冠心病（CHD）的风险显著增加。虽然饮食和运动可以改善IRS的某些表现，但通常需要药物治疗来使其他成分正常化。在我们实验室最近的研究中，烟酸和鱼油（n-3脂肪酸，FA）联合用于IRS个体改善了脂质表型，但出乎意料的是，膳食诱导的游离脂肪酸（FFA）通量抑制（脂肪组织胰岛素敏感性的重要指标）。本项目将探讨n-3 FA和烟酸联合（和单药）治疗对IRS受试者CHD危险因素、甘油三酯和FFA动力学以及葡萄糖处置率的临床疗效。我们将进行一项单次、随机、平行组、安慰剂对照试验。IRS受试者（根据NCEP ATP-itl指南）将在1个月的双重安慰剂导入期后随机分配至4个干预组之一。各组为：n-3 FA（3.4 g/d）、晶体烟酸（3 g/d）、复方制剂或duat安慰剂。后两组将各包括20例受试者，而两个单药治疗组将各包括10例受试者。将在基线和治疗4个月后确定对终点的影响。CHD危险因素包括血脂和脂蛋白;脂蛋白（a）; HDL和低密度脂蛋白的亚组分;组织纤溶酶原激活物和纤溶酶原激活物抑制剂-1;和血压。在空腹状态下、标准混合餐后和用于评价葡萄糖处置率的高胰岛素-正常血糖钳夹程序期间，通过推注2 H/5-甘油测定甘油三酯动力学，并通过使用3 H-棕榈酸酯恒定输注的同位素稀释测定FFA动力学。在这些研究完成后，我们期望获得关于这两种营养剂的潜在治疗功效和动力学作用机制的详细信息。这将导致更有效的治疗胰岛素抵抗的血脂异常，并最终降低冠心病的风险，在这个新兴的患者群体。

DESCRIPTION (provided by applicant): The insulin resistance syndrome (IRS) afflicts approximately 47 million Americans. Its principal components include central obesity, elevated triglycerides, decreased high density lipoprotein cholesterol (HDL-C) levels, fasting hyperglycemia, and/or hypertension. Individuals with the IRS are at significantly increased risk for developing type 2 diabetes mellitus and/or coronary heart disease (CHD). While diet and exercise can improve some manifestations of the IRS, pharmacotherapy is often needed to normalize other components. In recent studies from our laboratory, niacin and fish oil (n-3 fatty acids, FA) used in combination in individuals with the IRS improved the lipid phenotype, but also, unexpectedly, the mealinduced suppression of free fatty acid (FFA) flux (an important indicator of adipose tissue insulin sensitivity). This project will explore the clinical efficacy of combined (and mono-) therapy with n-3 FA and niacin on CHD risk factors, on triglyceride and FFA kinetics and on glucose disposal rates in subjects with the IRS. We will conduct a single, randomized, parallel-arm, placebo-controlled trial. Subjects with the IRS (per the NCEP ATP-itl guidelines) will be randomly allocated to one of four intervention groups after a one-month dual placebo run-in period. The groups will be: n-3 FA (3.4 g/d), crystalline niacin (3 g/d), the combination, or duat placebo. The latter two groups will include 20 subjects each while the two-monotherapy arms will have 10 subjects each. Effects on endpoints will be determined at baseline and after four months of treatment. The CHD risk factors include serum lipids and lipoproteins; lipoprotein(a); subfractions of HDL and of low density tipoproteins; tissue plasminogen activator and plasminogen activator inhibitor-1; and blood pressure. Triglyceride kinetics will be determined by bolus injection of 2H/5-glycerol, and FFA kinetics by isotope dilution using a constant infusion of 3H-palmitate in the fasting state, after a standard mixed meal and during the hyperinsulinemic-euglycemic clamp procedure used to evaluate glucose disposal rates. At the completion of these studies, we expect to have detailed information on the potential therapeutic efficacy and the kinetic mechanisms of action of these two nutritional agents. This should lead to more effective therapy for the dyslipidemia of insulin resistance and ultimately to reduced risk for CHD in this burgeoning patient population.