The University of Texas Health Science Center at San Antonio, Diabetes Division, Room 3.380S, 7703 Floyd Curl Drive, San Antonio, Texas 78284-3900, USA.
J Clin Endocrinol Metab. 2010 Feb;95(2):829-36. doi: 10.1210/jc.2009-1487. Epub 2010 Jan 8.
Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist widely used in clinical practice, but its mechanism of action is incompletely understood.
The aim of the study was to assess whether improvement in subclinical inflammation or glucose metabolism contributes to its antiatherogenic effects in insulin-resistant subjects with the metabolic syndrome (MetS).
We conducted a randomized, double-blind, placebo-controlled study in the research unit at an academic center.
We studied 25 nondiabetic insulin-resistant MetS subjects.
INTERVENTION(S): We administered fenofibrate (200 mg/d) and placebo for 12 wk.
Before and after treatment, we measured plasma lipids/apolipoproteins, inflammatory markers (high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule/vascular cell adhesion molecule), adipocytokines (adiponectin, TNFalpha, leptin), and insulin secretion (oral glucose tolerance test). We also assessed adipose tissue, hepatic and peripheral (muscle) insulin resistance fasting and during a euglycemic insulin clamp with (3)H glucose and (14)C palmitate infusion combined with indirect calorimetry.
Subjects displayed severe insulin resistance and systemic inflammation. Fenofibrate significantly reduced plasma triglyceride, apolipoprotein (apo) CII, apo CIII, and apo E (all P < 0.01), with a modest increase in high-density lipoprotein-cholesterol (+12%; P = 0.06). Fenofibrate markedly decreased plasma high-sensitivity C-reactive protein by 49.5 +/- 8% (P = 0.005) and IL-6 by 29.8 +/- 7% (P = 0.03) vs. placebo. However, neither insulin secretion nor adipose tissue, hepatic or muscle insulin sensitivity or glucose/lipid oxidation improved with treatment. Adiponectin and TNF-alpha levels were also unchanged. Improvement in plasma markers of vascular/systemic inflammation was dissociated from changes in triglyceride/high-density lipoprotein-cholesterol, apo CII/CIII, or free fatty acid concentrations or insulin secretion/insulin sensitivity.
In subjects with the MetS, fenofibrate reduces systemic inflammation independent of improvements in lipoprotein metabolism and without changing insulin sensitivity. This suggests a direct peroxisome proliferator-activated receptor alpha-mediated effect of fenofibrate on inflammatory pathways, which may be important for the prevention of CVD in high-risk patients.
非诺贝特是一种过氧化物酶体增殖物激活受体 α 激动剂，广泛应用于临床实践，但它的作用机制尚不完全清楚。
本研究旨在评估改善亚临床炎症或葡萄糖代谢是否有助于过氧化物酶体增殖物激活受体 α 激动剂非诺贝特在代谢综合征（MetS）合并胰岛素抵抗患者中的抗动脉粥样硬化作用。
我们在学术中心的研究单位进行了一项随机、双盲、安慰剂对照研究。
我们研究了 25 例非糖尿病胰岛素抵抗 MetS 患者。
我们给予非诺贝特（200mg/d）和安慰剂治疗 12 周。
治疗前后，我们测量了血浆脂质/载脂蛋白、炎症标志物（高敏 C 反应蛋白、IL-6、细胞间黏附分子/血管细胞黏附分子）、脂肪细胞因子（脂联素、TNFalpha、瘦素）和胰岛素分泌（口服葡萄糖耐量试验）。我们还评估了脂肪组织、肝脏和外周（肌肉）胰岛素抵抗，在进行正葡萄糖胰岛素钳夹时，通过（3）H 葡萄糖和（14）C 棕榈酸输注联合间接测热法评估。
患者表现出严重的胰岛素抵抗和全身炎症。非诺贝特显著降低了血浆甘油三酯、载脂蛋白（apo）CII、apo CIII 和 apo E（均 P < 0.01），高密度脂蛋白胆固醇增加了 12%（P = 0.06）。非诺贝特使血浆高敏 C 反应蛋白降低 49.5±8%（P = 0.005），IL-6 降低 29.8±7%（P = 0.03），安慰剂组无变化。然而，胰岛素分泌、脂肪组织、肝脏或肌肉胰岛素敏感性或葡萄糖/脂质氧化均未得到改善。脂联素和 TNFalpha 水平也没有变化。血管/全身炎症标志物的改善与甘油三酯/高密度脂蛋白胆固醇、apo CII/CIII 或游离脂肪酸浓度或胰岛素分泌/胰岛素敏感性的变化无关。
在 MetS 患者中，非诺贝特降低全身炎症，改善脂蛋白代谢，不改变胰岛素敏感性。这表明非诺贝特通过过氧化物酶体增殖物激活受体 α 直接作用于炎症途径，这可能对高危患者预防 CVD 很重要。
