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）折磨着大约4700万美国人。其主要成分包括中枢性肥胖、甘油三酯升高、高密度脂蛋白胆固醇（HDL-C）水平降低、空腹高血糖和/或高血压。IRS患者发生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）联合使用在患有IRS的个体中改善了脂质表型，但出乎意料的是，膳食诱导的游离脂肪酸（FFA）通量的抑制（脂肪组织胰岛素敏感性的重要指标）。该项目将探讨n- 3fa和烟酸联合（或单独）治疗对冠心病危险因素、甘油三酯和FFA动力学以及IRS受试者葡萄糖处置率的临床疗效。我们将进行一项单、随机、平行、安慰剂对照试验。IRS受试者（根据NCEP atp - 1指南）将在一个月的双安慰剂磨合期后随机分配到四个干预组中的一个。这些组将是：n- 3fa (3.4 g/d)，结晶烟酸（3g /d），组合或双重安慰剂。后两组各有20名受试者，而单药治疗组各有10名受试者。对终点的影响将在基线和治疗4个月后确定。冠心病危险因素包括血脂和脂蛋白；脂蛋白(a);高密度脂蛋白和低密度脂蛋白亚组分；组织纤溶酶原激活剂和纤溶酶原激活剂抑制剂-1；还有血压。甘油三酯动力学将通过注射2H/5-甘油来确定，FFA动力学将通过同位素稀释来确定，在空腹状态下，在标准混合餐后，在用于评估葡萄糖处置率的高胰岛素-血糖钳夹过程中，使用3h -棕榈酸盐持续输注。在这些研究完成后，我们期望对这两种营养制剂的潜在治疗效果和作用动力学机制有详细的了解。这将为胰岛素抵抗的血脂异常提供更有效的治疗方法，并最终降低这一新兴患者群体患冠心病的风险。

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.