Boden G, Chen X, Ruiz J, White J V, Rossetti L
Division of Endocrinology/Metabolism, Temple University School of Medicine, Philadelphia, Pennsylvania 19140.
J Clin Invest. 1994 Jun;93(6):2438-46. doi: 10.1172/JCI117252.
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 (approximately 50, approximately 550, approximately 750 microM) on rates of glucose uptake, glycolysis (both with 3-3H-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 approximately 50 to approximately 750 microM) decreased glucose uptake in a dose-dependent fashion (from approximately 9 to approximately 4 mg/kg per min). The decrease was caused mainly (approximately 2/3) by a reduction in glycogen synthesis and to a lesser extent (approximately 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 (approximately 750 microM), 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 (approximately 550 microM) 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 approximately 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.
血浆游离脂肪酸（FFA）水平升高会降低胰岛素刺激的葡萄糖摄取。然而，导致这种抑制作用的机制仍不明确。本研究的目的是确定FFA的作用是否呈剂量依赖性，并探究其机制。我们在健康志愿者（13名男性/1名女性）中研究了三种稳态血浆FFA水平（约50、约550、约750微摩尔/升）在正常血糖-高胰岛素钳夹期间对葡萄糖摄取率、糖酵解（均使用3-3H-葡萄糖）、糖原合成（用两种独立方法测定）、碳水化合物（CHO）氧化（通过间接测热法）、肝脏葡萄糖输出以及非氧化糖酵解（糖酵解减去CHO氧化）的影响。FFA浓度升高（从约50微摩尔/升增至约750微摩尔/升）会以剂量依赖方式降低葡萄糖摄取（从约9毫克/千克每分钟降至约4毫克/千克每分钟）。这种降低主要（约2/3）是由糖原合成减少引起的，在较小程度上（约1/3）是由CHO氧化减少导致的。我们发现糖原合成存在两个独立缺陷。第一个缺陷是肌肉糖原合酶活性受损。这需要高FFA浓度（约750微摩尔/升），与6-磷酸葡萄糖增加有关，且在脂肪输注4 - 6小时后出现。第二个缺陷在中等（约550微摩尔/升）FFA浓度时出现，先于糖原合酶缺陷，与肌肉6-磷酸葡萄糖浓度降低有关，可能是由于葡萄糖转运/磷酸化减少所致。此外，FFA和/或甘油使胰岛素抑制的肝脏葡萄糖输出增加约50%。我们得出结论，脂肪酸会导致胰岛素刺激的葡萄糖摄取呈剂量依赖性抑制（通过降低糖原合成和CHO氧化），并且FFA和/或甘油会增加胰岛素抑制的肝脏葡萄糖输出，从而在周围和肝脏水平引起胰岛素抵抗。
