Niacin, n-3 fatty acids and insulin resistance

描述(申请人提供)：胰岛素抵抗综合症(IRS)困扰着大约4700万美国人。其主要成分包括中心性肥胖、甘油三酯升高、高密度脂蛋白胆固醇(HDL-C)水平降低、空腹高血糖和/或高血压。患有IRS的人患2型糖尿病和/或冠心病(CHD)的风险显著增加。虽然饮食和锻炼可以改善IRS的一些表现，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)与IRS联合使用不仅改善了脂肪表型，而且出人意料地抑制了膳食诱导的游离脂肪酸(FFA)通量(脂肪组织胰岛素敏感性的重要指标)。本项目将探索n-3FA和烟酸联合(和单独)治疗对冠心病危险因素、对甘油三酯和FFA动力学的影响以及对IRS受试者的葡萄糖处理率的临床疗效。我们将进行一项单一、随机、平行对照、安慰剂对照的试验。在为期一个月的双重安慰剂试入期后，有IRS的受试者(根据NCEP ATP-ITL指南)将被随机分配到四个干预组中的一个。这些组将是：N-3FA(3.4g/d)，结晶烟酸(3g/d)，组合，或DUAT安慰剂。后两组每组将包括20名受试者，而两个单一疗法组将每组10名受试者。对终点的影响将在基线和治疗四个月后确定。冠心病的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的亚组分；组织纤溶酶原激活物和纤溶酶原激活物抑制物-1；以及血压。甘油三酯的动力学将通过团注2H/5-甘油来确定，而FFA的动力学将通过在禁食状态下、在标准的混合餐后以及在用于评估葡萄糖处置速率的高胰岛素-正常血糖钳夹过程中通过持续输注~3H-棕榈酸酯的同位素稀释法来确定。在这些研究完成后，我们希望对这两种营养剂的潜在治疗效果和作用的动力学机制有详细的信息。这将导致对胰岛素抵抗的血脂异常进行更有效的治疗，并最终降低这一迅速增长的患者群体中患冠心病的风险。

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.