The role of intramuscular lipid in insulin resistance
The role of intramuscular lipid in insulin resistance
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DOI：
10.1046/j.1365-201x.2003.01162.x
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发表时间：
2003-08-01
期刊：
影响因子：
--
通讯作者：
Kraegen, EW
中科院分区：
文献类型：
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作者：
Hegarty, BD;Furler, SM;Kraegen, EW
人们感兴趣的是脂肪代谢的改变如何导致肌肉的胰岛素抵抗。许多动物和人类的胰岛素抵抗状态都增加了肌肉甘油三酯的含量，现在肌肉脂肪积累和胰岛素抵抗之间存在可信的机制联系，这超出了经典的葡萄糖-脂肪酸循环。我们推测，肌肉中代谢活性的长链脂肪酰基COA(LCACoA)的胞浆积聚参与了这一过程，导致胰岛素抵抗和受损的胰岛素信号或酶活性(例如糖原合成酶或己糖激酶)，或者直接或通过蛋白激酶C(特别是PKC theta和epsilon)等介体的慢性移位/激活。神经酰胺和二酰甘油(DAGs)也与脂肪诱导的肌肉胰岛素抵抗的形式有关。饮食脂肪诱导的啮齿动物肌肉胰岛素抵抗相对容易通过减少胞质脂肪堆积的操作(例如，改变饮食、锻炼或禁食)来逆转。PPAR激动剂(伽马和阿尔法)也可以降低肌肉LCACoA并增强胰岛素敏感性。AICAR激活AMP激活的蛋白激酶(AMPK)可增强肌肉(尤其是糖酵解肌肉)对胰岛素的敏感性，但其与脂代谢改变的关系尚不明确。在啮齿类动物中，3-5小时急性游离脂肪酸升高、1-4天静脉输注葡萄糖或几周高脂饮食诱导的肌肉脂肪堆积/PKC转位/胰岛素信号改变/胰岛素抵抗的模式是相似的。最近的研究扩展了研究结果，并显示出与人类的相关性。通过增加进入肌肉的脂肪酸流量，或通过减少脂肪酸氧化，肌肉胞浆中的脂类可以积累。在某些情况下，肌肉胰岛素抵抗可能是一种适应，以优化脂肪酸的使用，因为它们是主要的可用能量燃料。这里描述的相互作用是基于肌肉脂代谢变化优化胰岛素抵抗治疗的基础。
There is interest in how altered lipid metabolism could contribute to muscle insulin resistance. Many animal and human states of insulin resistance have increased muscle triglyceride content, and there are now plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic glucose-fatty acid cycle. We postulate that muscle cytosolic accumulation of the metabolically active long-chain fatty acyl CoAs (LCACoA) is involved, leading to insulin resistance and impaired insulin signalling or impaired enzyme activity (e.g. glycogen synthase or hexokinase) either directly or via chronic translocation/activation of mediators such as a protein kinase C (particularly PKC theta and epsilon). Ceramides and diacylglycerols (DAGs) have also been implicated in forms of lipid-induced muscle insulin resistance. Dietary lipid-induced muscle insulin resistance in rodents is relatively easily reversed by manipulations that lessen cytosolic lipid accumulation (e.g. diet change, exercise or fasting). PPAR agonists (both gamma and alpha) also lower muscle LCACoA and enhance insulin sensitivity. Activation of AMP-activated protein kinase (AMPK) by AICAR leads to muscle enhancement (especially glycolytic muscle) of insulin sensitivity, but involvement of altered lipid metabolism is less clear cut. In rodents there are similarities in the pattern of muscle lipid accumulation/PKC translocation/altered insulin signalling/insulin resistance inducible by 3-5-h acute free fatty acid elevation, 1-4 days intravenous glucose infusion or several weeks of high-fat feeding. Recent studies extend findings and show relevance to humans. Muscle cytosolic lipids may accumulate either by increased fatty acid flux into muscle, or by reduced fatty acid oxidation. In some circumstances muscle insulin resistance may be an adaptation to optimize use of fatty acids when they are the predominant available energy fuel. The interactions described here are fundamental to optimizing therapy of insulin resistance based on alterations in muscle lipid metabolism.