Kraegen E W, Cooney G J, Ye J, Thompson A L
Garvan Institute of Medical Research, St Vincent's Hospital. Sydney NSW, Australia.
Exp Clin Endocrinol Diabetes. 2001;109(4):S516-26. doi: 10.1055/s-2001-15114.
There is now much interest in the mechanisms by which altered lipid metabolism might contribute to insulin resistance as is found in Syndrome X or in Type II diabetes. This review considers recent evidence obtained in animal models and its relevance to humans, and also likely mechanisms and strategies for the onset and amelioration of insulin resistance. A key tissue for development of insulin resistance is skeletal muscle. Animal models of Syndrome X (eg high fat fed rat) exhibit excess accumulation of muscle triglyceride coincident with development of insulin resistance. This seems to also occur in humans and several studies demonstrate increased muscle triglyceride content in insulin resistant states. Recently magnetic resonance spectroscopy has been used to demonstrate that at least some of the lipid accumulation is inside the muscle cell (myocyte). Factors leading to this accumulation are not clear, but it could derive from elevated circulating free fatty acids, basal or postprandial triglycerides, or reduced muscle fatty acid oxidation. Supporting a link with adipose tissue metabolism, there appears to be a close association of muscle and whole body insulin resistance with the degree of abdominal obesity. While causal relationships are still to be clearly established, there are now quite plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic Randle glucose-fatty acid cycle. In animal models, dietary changes or prior exercise which reduce muscle lipid accumulation also improve insulin sensitivity. It is likely that cytosolic accumulation of the active form of lipid in muscle, the long chain fatty acyl CoAs, is involved, leading to altered insulin signalling or enzyme activities (eg glycogen synthase) either directly or via chronic activation of mediators such as protein kinase C. Unless there is significant weight loss, short or medium term dietary manipulation does not alter insulin sensitivity as much in humans as in rodent models, and there is considerable interest in pharmacological intervention. Studies using PPARgamma receptor agonists, the thiazolidinediones, have supported the principle that reduced muscle lipid accumulation is associated with increased insulin sensitivity. Other potent systemic lipid-lowering agents such as PPARalpha receptor agonists (eg fibrates) or antilipolytic agents (eg nicotinic acid analogues) might improve insulin sensitivity but further work is needed, particularly to clarify implications for muscle metabolism. In conclusion, evidence is growing that excess muscle and liver lipid accumulation causes or exacerbates insulin resistance in Syndrome X and in Type II diabetes; development of strategies to prevent this seem very worthwhile.
目前，人们对脂质代谢改变可能导致胰岛素抵抗的机制非常感兴趣，这种胰岛素抵抗在X综合征或II型糖尿病中很常见。本综述考虑了在动物模型中获得的最新证据及其与人类的相关性，以及胰岛素抵抗发生和改善的可能机制和策略。骨骼肌是胰岛素抵抗发展的关键组织。X综合征的动物模型（如高脂喂养大鼠）表现出肌肉甘油三酯过度积累，同时伴有胰岛素抵抗的发展。这似乎在人类中也会发生，多项研究表明，在胰岛素抵抗状态下，肌肉甘油三酯含量会增加。最近，磁共振波谱已被用于证明至少部分脂质积累发生在肌肉细胞（肌细胞）内。导致这种积累的因素尚不清楚，但可能源于循环游离脂肪酸升高、基础或餐后甘油三酯升高，或肌肉脂肪酸氧化减少。支持与脂肪组织代谢存在联系的是，肌肉和全身胰岛素抵抗似乎与腹部肥胖程度密切相关。虽然因果关系仍有待明确确立，但目前肌肉脂质积累与胰岛素抵抗之间存在相当合理的机制联系，这超出了经典的兰德尔葡萄糖 - 脂肪酸循环。在动物模型中，饮食改变或先前的运动可减少肌肉脂质积累，同时也能改善胰岛素敏感性。肌肉中脂质活性形式长链脂肪酰辅酶A的胞质积累可能参与其中，直接或通过慢性激活蛋白激酶C等介质，导致胰岛素信号传导或酶活性（如糖原合酶）改变。除非体重显著减轻，短期或中期饮食控制对人类胰岛素敏感性的改善程度不如对啮齿动物模型，因此人们对药物干预非常感兴趣。使用PPARγ受体激动剂噻唑烷二酮类药物的研究支持了这样的原则，即减少肌肉脂质积累与提高胰岛素敏感性相关。其他强效的全身性降脂药物，如PPARα受体激动剂（如贝特类药物）或抗脂解药物（如烟酸类似物）可能会改善胰岛素敏感性，但还需要进一步研究，特别是要阐明对肌肉代谢的影响。总之，越来越多的证据表明，肌肉和肝脏脂质过度积累会导致或加剧X综合征和II型糖尿病中的胰岛素抵抗；制定预防这种情况的策略似乎非常值得。
