Mechanism of free fatty acid-induced insulin resistance in humans
Mechanism of free fatty acid-induced insulin resistance in humans
复制标题
DOI：
10.1172/jci118742
复制
发表时间：
1996-06-15
影响因子：
15.9
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Roden, M;Price, TB;Shulman, GI
为了研究脂质引起人类胰岛素抵抗的机制，在低浓度的胰岛素存在下，每15分钟通过同步C-13和P-31核磁共振光谱法测量9名健康受试者的骨骼肌糖原和葡萄糖-6-磷酸浓度。（0.18 +/- 0.02 mM [平均值+/- SEM];对照）或高（1.93 +/- 0.04 mM;正常血糖下血浆游离脂肪酸水平（类似于5.2 mM）高胰岛素血症在钳夹的最初3.5小时期间，全身葡萄糖摄取的速率不受脂质输注的影响，6 h后继续下降至对照值的46（P < 0.00001），在脂质输注的第3小时，脂质氧化增加伴随着氧化葡萄糖代谢减少约40%（P < 0.05），在脂质和对照输注的前3小时内，肌糖原合成速率相似，但此后降低至接近对照值的50%（4.0 +/- 1.0 vs，9.3 +/- 1.6 μ mol/[kg .血浆游离脂肪酸升高导致肌糖原合成减少，而肌葡萄糖-6-磷酸浓度在1.5 h左右开始下降（195 +/- 25 vs.对照：237 +/- 26 μ M; P < 0.01），因此，与最初假定的游离脂肪酸抑制胰岛素的机制相反，通过丙酮酸脱氢酶初始抑制刺激肌肉中的葡萄糖摄取这些结果证明游离脂肪酸通过葡萄糖转运/代谢的初始抑制诱导人的胰岛素抗性。磷酸化，随后是肌肉糖原合成和葡萄糖氧化速率的类似50%的降低。
To examine the mechanism by which lipids cause insulin resistance in humans, skeletal muscle glycogen and glucose-6-phosphate concentrations were measured every 15 min by simultaneous C-13 and P-31 nuclear magnetic resonance spectroscopy in nine healthy subjects in the presence of low (0.18 +/- 0.02 mM [mean +/- SEM]; control) or high (1.93 +/- 0.04 mM; lipid infusion) plasma free fatty acid levels under euglycemic (similar to 5.2 mM) hyperinsulinemic (similar to 400 pM) clamp conditions for 6 h, During the initial 3.5 h of the clamp the rate of whole-body glucose uptake was not affected by lipid infusion, but it then decreased continuously to be similar to 46% of control values after 6 h (P < 0.00001), Augmented lipid oxidation was accompanied by a similar to 40% reduction of oxidative glucose metabolism starting during the third hour of lipid infusion (P < 0.05), Rates of muscle glycogen synthesis were similar during the first 3 h of lipid and control infusion, but thereafter decreased to similar to 50% of control values (4.0 +/- 1.0 vs, 9.3 +/- 1.6 mu mol/[kg . min], P < 0.05), Reduction of muscle glycogen synthesis by elevated plasma free fatty acids was preceded by a fall of muscle glucose-6-phosphate concentrations starting at similar to 1.5 h (195 +/- 25 vs. control: 237 +/- 26 mu M; P < 0.01), Therefore in contrast to the originally postulated mechanism in which free fatty acids were thought to inhibit insulin-stimulated glucose uptake in muscle through initial inhibition of pyruvate dehydrogenase these results demonstrate that free fatty acids induce insulin resistance in humans by initial inhibition of glucose transport/phosphorylation which is then followed by an similar to 50% reduction in both the rate of muscle glycogen synthesis and glucose oxidation.