MECHANISMS OF FATTY ACID-INDUCED INHIBITION OF GLUCOSE-UPTAKE
MECHANISMS OF FATTY ACID-INDUCED INHIBITION OF GLUCOSE-UPTAKE
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DOI：
10.1172/jci117252
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发表时间：
1994-06-01
影响因子：
15.9
通讯作者：
ROSSETTI, L
中科院分区：
文献类型：
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作者：
BODEN, G;CHEN, XH;ROSSETTI, L
血浆游离脂肪酸增加减少胰岛素刺激的葡萄糖摄取。然而，这种抑制的机制仍然不确定。本研究的目的是确定FFA效应是否具有剂量依赖性，并研究其机制。我们在健康志愿者中进行了检查，（13只雄性/1只雌性）三种稳态血浆FFA水平的影响（类似于50，类似于550，类似于750 μ M）对葡萄糖摄取率，糖酵解（均与3-H-3-葡萄糖），糖原合成（用两种独立的方法测定）、碳水化合物（CHO）氧化（通过间接量热法）、肝葡萄糖输出和正常血糖-高胰岛素钳夹期间的非氧化糖酵解（糖酵解减去CHO氧化）。增加FFA浓度（从接近50 μ M到接近750 μ M）以剂量依赖性方式（从接近9 mg/kg/min到接近4 mg/kg/min）降低葡萄糖摄取。减少主要是由糖原合成减少引起的（类似于2/3），在较小程度上（类似于1/3）是由CHO氧化减少引起的。我们已经确定了两个独立的糖原合成缺陷。第一种是肌糖原合酶活性受损。它需要高FFA浓度（类似于750 μ M）与葡萄糖-6-磷酸的增加，并在4-6小时的脂肪输注后发展。第二个缺陷，这之前的糖原合酶缺陷，被认为是在中等（类似于550 μ M）FFA浓度，与肌肉葡萄糖-6-磷酸浓度的减少，可能是由于减少葡萄糖转运/磷酸化。此外，FFA和/或甘油使胰岛素抑制的肝葡萄糖输出增加了约50%。我们得出结论，脂肪酸引起胰岛素刺激的葡萄糖摄取的剂量依赖性抑制（通过减少糖原合成和CHO氧化），FFA和/或甘油增加胰岛素抑制的肝脏葡萄糖输出，从而引起外周和肝脏水平的胰岛素抵抗。
Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels (similar to 50, similar to 550, similar to 750 mu M) on rates of glucose uptake, glycolysis (both with 3-H-3-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from similar to 50 to similar to 750 mu M) decreased glucose uptake in a dose-dependent fashion (from similar to 9 to similar to 4 mg/kg per min). The decrease was caused mainly (similar to 2/3) by a reduction in glycogen synthesis and to a lesser extent (similar to 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration (similar to 750 mu M) was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium(similar to 550 mu M) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by similar to 50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level.