Free fatty acid-induced insulin resistance is associated with activation of protein kinase C θ and alterations in the insulin signaling cascade
Free fatty acid-induced insulin resistance is associated with activation of protein kinase C θ and alterations in the insulin signaling cascade
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DOI：
10.2337/diabetes.48.6.1270
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发表时间：
1999-06-01
期刊：
影响因子：
7.7
通讯作者：
Shulman, GI
中科院分区：
文献类型：
--
作者：
Griffin, ME;Marcucci, MJ;Shulman, GI
为了研究游离脂肪酸（FFA）在体内诱导胰岛素抵抗的机制，清醒的长期插管大鼠进行了高胰岛素-正葡萄糖钳夹，有或没有5小时的脂质/肝素预输注，以提高血浆FFA浓度。增加的血浆FFA导致胰岛素抵抗，如葡萄糖输注速率降低35%所反映的（与对照相比，P < 0.05）。胰岛素抵抗与C-13核磁共振（NMR）测定的肌糖原合成率降低40-50%相关（P < 0.01 vs，对照）和肌肉葡萄糖氧化（P < 0.01相对于对照），这又可归因于葡萄糖转运活性的类似于25%的降低，如通过2-[1，2-H-3]脱氧葡萄糖摄取（P < 0.05，与对照相比）。这种脂质诱导的胰岛素刺激的肌肉葡萄糖代谢的降低与1）胰岛素刺激的胰岛素受体底物（IRS）-1-相关的磷脂酰肌醇（PI）3-激酶活性降低约50%有关（与对照组相比P < 0.05），3）胰岛素刺激的IRS-1酪氨酸磷酸化的钝化（P < 0.05，脂质输注对比甘油输注），和3）膜结合或活性蛋白激酶C（PKC）θ增加四倍（P < 0.05对比对照）。我的结论是急性血浆FFA水平升高5小时诱导骨骼肌胰岛素抵抗在体内通过减少胰岛素刺激的肌糖原合成和葡萄糖氧化，可以归因于降低葡萄糖转运活性。这些变化与胰岛素信号级联反应异常有关，可能由FFA激活PKC θ介导。
To examine the mechanism by which free fatty acids (FFAs) induce insulin resistance in vivo, awake chronically catheterized rats underwent a hyperinsulinemic-euglycemic clamp with or without a 5-h preinfusion of lipid/heparin to raise plasma FFA concentrations. Increased plasma FFAs resulted in insulin resistance as reflected by a similar to 35% reduction in the glucose infusion rate (P < 0.05 vs. control). The insulin resistance was associated with a 40-50% reduction in C-13 nuclear magnetic resonance (NMR)-determined rates of muscle glycogen synthesis (P < 0.01 vs, control) and muscle glucose oxidation (P < 0.01 vs. control), which in turn could be attributed to a similar to 25% reduction in glucose transport activity as assessed by 2-[1,2-H-3]deoxyglucose uptake in vivo (P < 0.05 vs. control). This lipid-induced decrease in insulin-stimulated muscle glucose metabolism was associated with 1) a similar to 50% reduction in insulin-stimulated insulin receptor substrate (IRS)-1-associated phosphatidylinositol (PI) 3-kinase activity (P < 0.05 vs. control), 3) a blunting in insulin-stimulated IRS-1 tyrosine phosphorylation (P < 0.05, lipid-infused versus glycerol-infused), and 3) a fourfold increase in membrane-bound, or active, protein kinase C (PKC) theta (P < 0.05 vs. control). me conclude that acute elevations of plasma FFA levels for 5 h induce skeletal muscle insulin resistance in vivo via a reduction in insulin-stimulated muscle glycogen synthesis and glucose oxidation that can be attributed to reduced glucose transport activity. These changes are associated with abnormalities in the insulin signaling cascade and may be mediated by FFA activation of PKC theta.