The molecular mechanism linking muscle fat accumulation to insulin resistance
The molecular mechanism linking muscle fat accumulation to insulin resistance
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DOI：
10.1079/pns2004351
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发表时间：
2004-05-01
影响因子：
7
通讯作者：
Dohm, GL
中科院分区：
文献类型：
--
作者：
Hulver, MW;Dohm, GL
骨骼肌胰岛素抵抗是肥胖的共病，也是发展为2型糖尿病的危险因素。胰岛素抵抗与肌细胞内脂质的积累有关。肌细胞内三酰甘油似乎不是胰岛素抵抗的原因，但更可能是其他脂质中间体如脂肪酰辅酶A、神经酰胺或二酰甘油的标志物。已知脂肪酰基辅酶A、神经酰胺和二酰基甘油直接改变胰岛素信号级联的各个方面。在胰岛素受体和胰岛素受体底物1水平上，丝氨酸和苏氨酸残基的磷酸化抑制胰岛素信号传导。蛋白激酶C负责丝氨酸和苏氨酸残基的磷酸化。已知脂肪酰基辅酶A和二酰基甘油可激活蛋白激酶C。目前尚不清楚肌细胞内脂肪酰辅酶A和二酰甘油蓄积的原因。脂肪酸氧化减少似乎不是原因，因为脂肪酰辅酶A在具有正常脂肪酸氧化能力的骨骼肌中积累。其他潜在的机制包括脂质向肌肉过度供应和/或上调脂肪酸转运。
Skeletal muscle insulin resistance is a co-morbidity of obesity and a risk factor for the development of type 2 diabetes mellitus. Insulin resistance is associated with the accumulation of intramyocellular lipids. Intramyocellular triacylglycerols do not appear to be the cause of insulin resistance but are more likely to be a marker of other lipid intermediates such as fatty acyl-CoA, ceramides or diacylglycerols. Fatty acyl-CoA, ceramides and diacylglycerols are known to directly alter various aspects of the insulin signalling cascade. Insulin signalling is inhibited by the phosphorylation of serine and threonine residues at the levels of the insulin receptor and insulin receptor substrate 1. Protein kinase C is responsible for the phosphorylation of the serine and threonine residues. Fatty acyl-CoA and diacylglycerols are known to activate protein kinase C. The cause of the intramyocellular accumulation of fatty acyl-CoA and diacylglycerols is unclear at this time. Reduced fatty acid oxidation does not appear to be responsible, as fatty acyl-CoA accumulates in skeletal muscle with a normal fatty acid oxidative capacity. Other potential mechanisms include oversupply of lipids to muscle and/or up regulated fatty acid transport.